Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:17])[N:10]([C@@H:18]3[O:35][C@H:34]([CH2:36][O:37]C(=O)C)[C@@H:29]([O:30]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@H:19]3[O:20]C(=O)C)[CH:9]=2)=[CH:4][CH:3]=1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH3:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:8]([CH2:7][C:5]1[S:6][C:2]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:3][CH:4]=1)=[CH:9][N:10]2[C@@H:18]1[O:35][C@H:34]([CH2:36][OH:37])[C@@H:29]([OH:30])[C@H:24]([OH:25])[C@H:19]1[OH:20]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(Br)s3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cccc2c1c(Cc1ccc(-c3ccccc3)s1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
3-(5-Bromothiophen-2-yl-methyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 45-(3) and benzeneboronic acid were treated in a manner similar to Example 45-(4) and 2-(7) to give the titled compound as a pale yellow powder. APCI-Mass m/Z 466 (M+H). 1H-NMR (DMSO-d6) δ 2.50 (s, 3H), 3.25 (m, 1H), 3.35-3.49 (m, 2H), 3.66-3.73 (m, 2H), 4.38 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.17 (d, J=5.9 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 6.75 (d, J=7.1 Hz, 1H), 6.80 (d, J=3.5 Hz, 1H), 7.00 (t, J=7.6 Hz, 1H), 7.24 (t, J=7.3 Hz, 1H), 7.31-7.38 (m, 5H), 7.56 (d, J=7.4 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.CCCCCC.C([Li])CCC.Cl[C:31]([O:33][CH3:34])=[O:32]>C(OCC)C>[F:16][CH2:15][C:10]([CH2:11][F:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[C:13]#[C:14][C:31]([O:33][CH3:34])=[O:32]
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
An amount (0.53 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in diethyl ether (3 ml); to the solution under cooling with ice, a hexane solution (1.4 ml) of 1.69 M n-butyllithium was added dropwise under a nitrogen atmosphere. After the end of the dropwise addition, the mixture was stirred for 1 hour under cooling with ice. The resulting mixture was added dropwise to a solution of methyl chloroformate (0.38 g) in diethyl ether (3 ml) under a nitrogen atmosphere under cooling with ice. After stirring the mixture for 1 hour under cooling with ice, hexane was added, followed by washing with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (0.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[C:18]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH2:18])=[CH:4][CH:3]=1
Reactant: CC(C)C(C)(C)C(=O)CCc1ccc(Cl)cc1
Reactant: Cc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(CCc1ccc(Cl)cc1)C(C)(C)C(C)C
Temperature: 25 °C
Yield: 58 %

Procedure:
A suspension of 47.4 g (0.133 mol) of methyltriphenyl-phosphonium bromide and 15.3 g (0.137 mol) of potassium tert.-butylate in 250 ml of absolute toluene is heated under reflux under dry nitrogen 25.2 g (0.1 mol) of 1-(4-chlorophenyl)-4,4,5-trimethyl-hexan-3-one are introduced over the course of 5 minutes The reaction mixture is heated under reflux for a further 15 hours, then cooled to room temperature, washed twice with water and concentrated under reduced pressure The residue is taken up in ethyl acetate, cooled to 5° C. and the crop of crystals formed is filtered off with suction. The filtrate is concentrated and distilled under reduced pressure. 14.5 g (58% of theory) of 2-(4-chlorophenylethyl)-3,3,4-trimethyl-pent-1-ene are obtained in the form of a yellow oil of boiling point 88°-90° C./0.1 mbar. ##STR22##
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH2:24][OH:25])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=[O:25])[C:21]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:20]4)=[CH:31][CH:32]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: O=Cc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of [1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]methanol (2.03 g), activated manganese dioxide (6.00 g), and tetrahydrofuran (50 ml) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.74 g, yield: 86%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 153˜154° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:23].[Na+].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:12][CH:13]=3)[C:8](=[O:23])[C:7]=2[CH:6]=1)=[O:4]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1-2
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)c1ccc2c(c1)C(=O)c1cc(C(=O)CCl)ccc1-2

Procedure:
A mixture of 5.0g (0.016 mole) of 2,7-bis(chloroacetyl)fluorene, 6.3g (0.020 mole) of sodium dichromate and 125 ml of glacial acetic acid was refluxed with stirring for seventeen hours. The resulting precipitate was filtered while the solution was hot, then washed with acetic acid and dried in vacuo to yield the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[O:7]=[C:8]1[NH:16][CH:15]=[N:14][C:13]2[N:12]([CH2:17][CH2:18][C:19](OCC)=[O:20])[CH:11]=[N:10][C:9]1=2>C(#N)C.CO>[O:7]=[C:8]1[NH:16][CH:15]=[N:14][C:13]2[N:12]([CH2:17][CH2:18][C:19]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[O:20])[CH:11]=[N:10][C:9]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCC(O)CO
Solvent: CC#N
Solvent: CO
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCC(O)CO
Temperature: 110 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
0.500 g (5.49 mmol) of 3-amino-1,2-propanediol was placed into a 10 ml round bottom flask with a magnetic stirring bar. The flask was heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was stirred at 100°-110° C. for one hour. The flask was allowed to cool to room temperature and 10 ml of 1:1 acetonitrile/methanol was added and the solution was stirred vigorously for 30 minutes. The resulting white precipitate was collected using Buchner funnel filtration to yield 272 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(2,3-dihydroxyprop-1-yl)propanamide (AIT-0062) as a white solid. 91% yield.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].ClCl.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: Oc1ccccc1
Agent: ClCl
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 80 °C
Reaction time: 5 h
Yield: 14.5 %

Procedure:
2.00 g (20 mmol) of hydantoin was dissolved in 30 ml of acetic acid. The solution was then heated to a temperature of 80° C. under stirring with chlorine being introduced thereinto for 5 hours. The reaction system was then allowed to cool to room temperature. The dissolved chlorine was then removed by introducing nitrogen into the reaction system. To the reaction solution was then added 3.76 g (40 mmol) of phenol. The reaction mixture was then heated to a temperature of 70° C. for 8 hours. The reaction solution was then allowed to cool to room temperature. The reaction solution was then concentrated under reduced pressure to distill off acetic acid and phenol. To the resulting residue was then added 50 ml of water. The mixture was then heated to effect dissolution. The solution was then allowed to stand. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 0.55 g (2.89 mmol; yield: 28.9%) of 5-(p-hydroxyphenyl)hydantoin in the form of white flake crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>CN(C)C1C=CN=CC=1.ClCCCl>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:24]([N:5]2[CH2:6][CH2:7][CH2:8][C:2]([CH3:16])([CH3:1])[C:3]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]2=3)=[O:25])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1(C)CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 41 h
Yield: 46 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.797 g, 3.62 mmol), Pyridine (6.310 mL, 3.83 mmol) and 4-Dimethylaminopyridine (21 mg, 0.17 mmol) were dissolved in anhydrous 1,2-Dichloroethane (5.0 mL) before adding p-Nitrophenyl Chloroformate (0.541 g, 2.68 mmol). The reaction was stirred at room temperature for 41 hours and then concentrated under reduced pressure. The residue was purified by normal phase chromatography to yield an off-white solid, 5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 4-nitro-phenyl ester (0.475 g, 46%). LCMS: m/z=386.07 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.21 (m, 4H), 7.65 (d, 1H, J=8.8 Hz), 7.42 (m, 1H), 7.23 (m, 1H), 4.53 (m, 1H), 2.87 (m, 1H), 2.32 (m, 1H), 1.69 (m, 5H), 1.34 (m, 4H).
Reaction SMILES: Br[C:2]([CH3:14])([CH2:12]Br)[C:3](=[NH:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([O:25][CH:12]=[C:2]([CH3:14])[C:3](=[N:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CC(Br)(CBr)C(=N)Oc1ccccc1
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC=C(C)C(=Nc2ccccc2)Oc2ccccc2)cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
To a solution of 1.0 g (2.51 mmol) of phenyl 2,3-dibromo-2-methylpropanimidate and 466 mg (3.02 mmol) of 3,4-dimethoxyphenol in 5 ml of DMF was added 2.05 g (6.29 mmol) of cesium carbonate and stirred at 70° C. for 5 hours. After cooling to room temperature, the reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed sequentially with water and a saturated NaCl, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 252 mg of phenyl 3-(3,4-dimethoxyphenyloxy)-2-methyl-N-phenyl-2-propenimidate (hereinafter referred to as the present compound 99) and 145 mg of 3,4-dimethoxyphenyl 3-(3,4-dimethoxyphenyloxy)-2-methyl-N-phenyl-2-propenimidate (hereinafter referred to as the present compound 100).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[O:7][N:6]=[C:5]([CH:8](O)[CH3:9])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:33]>C(OCC)C>[Br:33][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[O:7][N:6]=1)[CH3:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)c1cc(C(F)(F)F)on1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(Br)c1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(5-Trifluoromethyl-isoxazol-3-yl)ethanol was dissolved in 35 ml of diethyl ether, and 2.93 g of triphenylphosphine and 3.71 g of carbon tetrabromide were then added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was subjected to silica gel column chromatography to obtain 1.14 g of 3-(1-bromoethyl)-5-trifluoromethylisoxazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH:11][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cccc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1c(F)cccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 2-benzyloxy-6-fluoroaniline (950 mg, 4.37 mmol), methyl bromoacetate (456 μL, 737 mg, 4.82 mmol), and potassium carbonate (1.21 g, 8.76 mmols) in DMF (10 mL) is heated at 60° C. for 18 h. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The organic layer is dried, filtered, and the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate) to afford methyl 2-(2-benzyloxy-6-fluoroanilino)-acetate as an oil. MS (M+1)+=290; NMR (CDCl3): δ 7.39 (m, 5H), 6.67 (m, 3H), 5.10 (s, 2H), 4.57 (br s, 1H), 4.11 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17]O)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][Br:2])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(CCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: BrCc1ccc(CCc2ccccc2)cc1
Reaction time: 2 h

Procedure:
3.14 ml (33.4 mmol) of phosphorus tribromide in 11 ml of toluene are added dropwise, while cooling and under an N2 atmosphere, to 8.36 g (85%; 33.4 mmol) of p-(2-phenylethyl)benzyl alcohol in 100 ml of toluene. After 2 h at RT, the mixture is poured onto ice-water and the organic phase is separated off; it is washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ether, and the combined organic phases are dried with Na2SO4 and evaporated: TLC Rf (A)=0.77; 1H-NMR (200 MHz, CDCl3): 2.92 (s, 4H), 4.50 (s, 2H), 7.15-7.35 (m, 9H); additional signals of approximately 20% p-(2-phenylethyl)toluene.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[NH2:50][CH:51]([CH:60]([OH:63])[CH2:61][F:62])[CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54]>C1COCC1>[C:1]([NH:11][C@H:12]([C:16]([NH:50][CH:51]([CH:60]([OH:63])[CH2:61][F:62])[CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[O:18])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
To a solution of Cbz-Valine (396 mg, 1.58 mmol) in THF (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (300 mg, 1.57 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (240 mg, 1.57 mmol) and dimethylaminopyridine (DMAP) 129 mg 1.06 mmol). The resulting mixture was stirred for 5 min, then was added a solution of t-butyl 3-amino-5-fluoro-4-hydroxy-pentanoate (215 mg, 1.04 mmol) in THF (10 mL) and it was stirred at rt for 18 h. The mixture was filtered and the THF solution was evaporated, and the residue was purified by chromatography over silica gel (hexane-EtOAc, 3:2) to give 290 mg (68%) of the titled compound as a white solid. 1HNMR (CDCl3), 0.905 (d, 3H, J=7), 0.965 (d, 3H, J=7), 1.428 (s, 9H), 2.07-2.16 (m, 1H), 2.50-2.57 (m, 1H), 2.64-2.70 (m, 1H), 3.52 (bs, 1H, OH), 3.92-3.96 (m, 2H), 4.20-4.27 (m, 1H), 4.40 (bs, 1H), 4.49 (bs, 1H), 5.10 (s, 2H), 5.31-5.4 (m, 1H, NH), 6.86-6.93 (m, 1H, NH), 7.350(s, 5H).
Reaction SMILES: I[CH:2]=[CH:3][C:4]1[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=1[CH3:11].[C:12]([C:14]1[CH:28]=[CH:27][C:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])=[CH:16][CH:15]=1)#[CH:13]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[CH3:11][C:5]1[CH2:6][CH2:7][CH2:8][C:9](=[O:10])[C:4]=1[CH:3]=[CH:2][C:13]#[C:12][C:14]1[CH:28]=[CH:27][C:17]([C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])=[CH:16][CH:15]=1
Reactant: C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Reactant: CC1=C(C=CI)C(=O)CCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1=C(C=CC#Cc2ccc(C(=O)OCC[Si](C)(C)C)cc2)C(=O)CCC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 1-iodo-2-(2-methyl-6-oxocyclohex-1-enyl)ethene (Compound E, available in accordance with the teachings of U.S. Pat. No. 5,760,276, 0.70 g, 2.67 mmol), (trimethylsilyl)ethyl 4-ethynylbenzoate (Compound C, 0.79 g, 3.21 mmol) and triethylamine (32 ml) was purged with argon for 10 minutes, and then treated with bis(triphenylphosphine)palladium (II) chloride (47 mg, 0.07 mmol) and copper (I) iodide (12.8 mg, 0.07 mmol). The solution was stirred 40° C. for 3 hours, and concentrated under a water aspirator vacuum. The residue was dissolved in ethyl acetate and washed with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (90:10, hexane:ethyl acetate) to give the title compound.
Reaction SMILES: C([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][NH:33]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:53]>>[ClH:53].[ClH:53].[ClH:53].[ClH:53].[NH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH2:20]
Reactant: c1ccc(C(NCCNCCCCCCNCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: NCCNCCCCCCNCCN

Procedure:
A mixture of N, N′-bis(2′-tritylaminoethyl)-1,6-diaminohexane (1.0 g 1.45 mmol) and 6 M HCl (30 ml) was refluxed for 3 h. The mixture was filtered and the filtrate was concentrated to about 3 ml over vacuao. Addition of methanol into the concentrated solution afforded a white salt.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH3:20]>C1COCC1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH:16]([C:15]1[CH:18]=[CH:19][C:12]([F:11])=[C:13]([CH3:20])[CH:14]=1)[OH:17]
Reactant: Cc1cc(C=O)ccc1F
Reactant: BrCCC1OCCO1
Agent: II
Solvent: C1CCOC1
Product: Cc1cc(C(O)CCC2OCCO2)ccc1F
Temperature: 63 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a suspension of Mg turnings (1.1 g, 0.05 g-at.) and catalytic amount of iodine in 200 mL THF was added dropwise 2-(2-bromoethyl)-[1,3]dioxolane (4.3 g, 0.02 mol) with heating over a period of 30 min. The resulting mixture was stirred for 30 min at 63° C. and then cooled to −30° C. and 4-fluoro-3-methyl-benzaldehyde (3.0 g, 0.02 mol) added slowly as a solution in 50 mL of THF. The temperature was maintained at −30° C. for 1 h and then slowly raised to room temperature over a period of 3 h. The excess Grignard was destroyed by the careful addition of 200 mL saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic layers washed with brine (2×50 mL) and dried over Na2SO4. After evaporation of the solvent, the product was isolated by flash column chromatography eluting with 0% to 50% ethyl acetate/hexanes to give 1.6 g of the title compounds as a light yellow oil.
Reaction SMILES: [Na].[F:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[F:10][C:11]1[C:12]([CH2:22]Br)=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].O>C(O)C>[F:10][C:11]1[C:12]([CH2:22][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cccc(F)c1CBr
Reactant: Oc1cccc(F)c1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cccc(F)c1COc1cccc(F)c1
Yield: 89.3 %

Procedure:
To a solution of 1.3 g of sodium metal in 100 ml of ethanol are added 6.3 g of 3-fluorophenol and 13 g of ethyl 3-fluoro-2-bromomethylbenzoate and the mixture is refluxed with heating for 8 hours. After cooling, 300 ml of water is added and the mixture is extracted with toluene. After the extract is washed with water and a saturated saline solution and dried over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is subjected to silica-gel chromatography and eluted with toluene to give 13 g of ethyl 3-fluoro-2-[(3-fluorophenyl oxy)methyl]benzoate (oil). Mass spectrum m/z: 292(M+).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([C:13]3[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1.[H-].[Na+].[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].O>CN(C=O)C>[CH2:31]([O:19][C:16]1[CH:15]=[N:14][C:13]([CH:9]2[C:10](=[O:12])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:18][CH:17]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(=O)C(c1ncc(O)cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2=O)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1-fluoro-3-octyloxy-6,7-dihydro-5H-isoquinolin-8-one.