Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22]1>C(#N)C>[NH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:22]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: NCC1CCNC1
Solvent: CC#N
Product: NCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 1.00 g (3.53 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 10 ml of acetonitrile, 0.54 g (3.5 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene, and 0.37 g (3.7 mmole) of 3-pyrrolidinemethanamine is refluxed one hour, then stirred at room temperature overnight. The reaction mixture is then filtered and the precipitate washed with ethyl ether until dry to yield 1.21 g (94.5%) of the title compound, mp 232°-235° C.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)[NH2:3]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1NN
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
9.71 g of hydrazine monohydrate was dissolved in 200 mL of ethanol, and cooled to 0° C. To this was added a solution prepared by dissolving 15.0 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate in 200 mL of ethanol, and stirred for 1 hour. The precipitated solid was taken out through filtration, washed with distilled water, and dried to obtain 9.66 g of the entitled compound as a white solid.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])=[CH:3]\[C:4]([NH2:6])=[O:5].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21].C(N(CC)CC)C>CO>[C:4](/[CH:3]=[C:2](\[CH3:1])/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:18])/[CH2:11][CH2:12][C:13](=[O:17])[CH:14]([CH3:16])[CH2:15][S:21][CH2:20][C:19]([O:23][CH3:24])=[O:22])(=[O:5])[NH2:6]
Reactant: COC(=O)CS
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.0 g (0.008 mol) of (E,E)-3,7,11-trimethyl-10-oxo-2,6,11-dodecatrienamide in 60 ml of methanol is treated with 2.3 ml of methyl thioglycolate and 3.4 ml of triethylamine. The solution is stirred at room temperature for 8 hours under argon. After removing the solvent the residue is taken up in water and methylene chloride. After extraction the organic phase is dried and freed from solvent. The residue is chromatographed on silica gel with ether-methanol 20:1. There is obtained methyl [[(6E,10E)-11-carbamoyl-2,6,10-trimethyl-3-oxo-6,10-undecadienyl]thio]acetate which exhibits the following absorption bands in the IR spectrum: 3447 cm-1, 3352 cm-1, 3195 cm-1, 1735 cm-1, 1712 cm-1, 1669 cm-1, 1638 cm-1 1609 cm-1, 1436 cm-1, 1300 cm-1, 1137 cm-1, 1008 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:17]=2)[CH:12]=[C:11]([C:30]2[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3cc(-c4cccnc4)nc(OCc4ccccc4)c3c2)c1

Procedure:
To a mixture of 1-(benzyloxy)-3-chloro-7-(3-methoxyphenyl)isoquinoline (150 mg, 0.40 mmol, 1.0 eq), pyridin-3-ylboronic acid (74 mg, 0.60 mmol, 1.5 eq), K2CO3 (166 mg, 1.20 mmol, 3.0 eq) in dioxane (2 ml) and H2O (1 mL) was added Pd(PPh3)2Cl2 (14 mg, 0.02 mmol, 0.05 eq) under N2 atmosphere. The sealed tube was irradiated in the CEM microwave at 130° C. for 1 h. After the reaction was completed, the volatiles were removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 50:1) to give 200 mg of crude lxvii-a as a brown oil, which was used directly in the next step without purification, LCMS m/z=419.0 (M+1) (Method B) (retention time=2.25 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[NH:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][N:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:14]=2[N:13]=[C:12]1[CH3:15]
Reactant: CCOC(=O)c1cccc2nc(C)[nH]c12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1nc(C)n2Cc1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of 1.61 g of 4-ethoxycarbonyl-2-methylbenzimidazole, 3.08 g of 2,4-dichlorobenzyl chloride, 1.51 g of potassium iodide, 1.05 g of potassium carbonate and 4 ml of N,N-dimethylformamide was stirred at 80° C. for 16 hours. The reaction mixture was extracted with chloroform and with water. The chloroform layer was washed with water, dried, and concentrated. The residue was purified through silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 2:8) to give 0.730 g of 1-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-2-methylbenzimidazole (297).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([N:10]1[C:14](=O)[CH2:13][O:12][C:11]1=[S:16])[CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C(OCC)(=O)C>[CH2:8]([N:10]1[C:14](=[S:26])[CH2:13][O:12][C:11]1=[S:16])[CH3:9]
Reactant: CCN1C(=O)COC1=S
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN1C(=S)COC1=S
Yield: 94 %

Procedure:
A toluene (10 mL) solution of 3-ethyl-2-thioxooxazolidin-4-one 3 (145 mg, 1.0 mmol) and Lawesson's reagent (607 mg, 1.5 mmol) was refluxed overnight. The solution was cooled and diluted with ethyl acetate (100 mL), then washed with water (2×20 mL). The organic layer was dried with brine and MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane:ethyl acetate=10:1), and the desired product 6 was obtained in 94% yield (152 mg, orange oil). 1H NMR (400 MHz, CDCl3): δ 5.12 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:12]1(=[O:16])[O:15][CH2:14][CH2:13]1>[OH-].[Na+].CCOCC>[Cl:10][C:9]1[C:2]([Cl:1])=[C:3]([CH:4]=[O:5])[CH:6]=[CH:7][C:8]=1[O:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15]
Reactant: O=C1CCO1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=Cc1ccc(OCCC(=O)O)c(Cl)c1Cl

Procedure:
2,3-dichloro-4-hydroxybenzaldehyde (38.2 g., 0.2 mole) is dissolved in a 10% sodium hydroxide solution (200 ml.). The solution is heated to boiling and β-propiolactone (144 g., 2.0 moles) is added dropwise at such a rate as to keep the solution boiling. During the addition 10% sodium hydroxide solution is added in portions to maintain an alkaline mixture. Then the solution is cooled and acidified. The precipitated material is dissolved in ether and the product is extracted into a 5% sodium bicarbonate solution. Acidification of the aqueous solution precipitates 3-(2,3-dichloro-4-formylphenoxy)propionic acid, which is purified by recrystallization from ethyl acetate.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.C(O)(=[O:16])C.[OH-].[Na+]>O>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([CH2:3][OH:16])[OH:4]
Reactant: CC(=O)O
Reactant: CCCCCCCCOCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCOCC(O)CO
Temperature: 200 °C
Reaction time: 1 h
Yield: 558 %

Procedure:
In a reactor, 390 g of octanol, 2 g of aluminum triisopropoxide and 1.4 g of sulfuric acid were charged. After heating to 100° C., dehydration was conducted under reduced pressure (2.67 kPa). The residue was then cooled to 85° C., followed by the dropwise addition of 185 g of epichlorohydrin at a temperature maintained at 85° C. After stirring at 85° C. for 4 hours, an excess alcohol was removed at 100° C. under reduced pressure (0.67 kPa). To the crude octyl halohydrin ether thus obtained, 480 g of a 209 aqueous solution of sodium hydroxide was added and the resulting mixture was reacted at 90° C. for 2 hours. After completion of the reaction, the water layer was removed, whereby 315 g of crude octyl glycidyl ether was obtained. In an autoclave, 200 g of the resulting crude octyl glycidyl ether, 35 g of water, 11.8 g of 99% acetic acid and 12.1 g of a 48% aqueous solution of sodium hydroxide were charged, followed by stirring at 200° C. for 1 hour. At a temperature maintained at 200° C., 27.5 g of a 48% aqueous solution of sodium hydroxide was added dropwise over 3 hours and reaction was conducted for 1 hour. The reaction mixture was cooled to 80° C. While maintaining the temperature at 80° C., 150 g of water was added and the resulting mixture was stirred vigorously. The reaction mixture was allowed to stand to cause separation, followed by removal of the water layer. The operation from the addition of 150 g of water to the separation was then repeated three times. The reaction mixture was dehydrated at 100° C. under reduced pressure (5.32 kPa), whereby 224 g of monooctyl glyceryl ether was obtained. As a result of GLC, it was found that the resulting product had a purity of 91% and the content of organochlorine compounds was not greater than 100 ppm.
Reaction SMILES: [ClH:1].CO[C:4](=O)[C@H:5]([CH2:7][CH2:8][CH2:9][NH2:10])[NH2:6].Cl.[S-:13][C:14]#[N:15].[K+].C(O)C>O>[ClH:1].[NH2:10][CH2:9][CH2:8][CH2:7][C:5]1[NH:6][C:14](=[S:13])[NH:15][CH:4]=1
Reactant: N#C[S-]
Reactant: COC(=O)[C@@H](N)CCCN
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NCCCc1c[nH]c(=S)[nH]1
Temperature: 5 °C

Procedure:
To an Erlenmeyer flask was prepared a solution of L-ornithine methyl ester hydrochloride (10.50 g, 47.9 mmol) in water (125 mL) The solution was cooled to 5° C. and pH adjusted to a value of 1.5 with concentrated HCl. While being careful to maintain the above stated temperature and pH, 5% Na(Hg) (250 g) was added slowly to the solution over a time period of 35 min After the addition was complete and bubbling had calmed the Hg was decanted from the solution. The remaining aqueous portion was drained into a separate flask where potassium thiocyanate (14.0 g, 144 mmol) and water (75 mL) was added. The pH of solution was adjusted to a value of 4.30 and the flask was then heated at 95° C. while open to the atmosphere for 1.5 h. After cooling to room temperature, ethanol (75 mL) was added and the reaction was evaporated to dryness. The residue was taken up in methanol and filtered to remove NaCl. After all of the NaCl had been removed the crude residue was purified by column chromatography (CH2Cl2/MeOH sat. with NH3 80:20) to afford the desired compound in its free base form. Addition of concentrated hydrochloric acid to a methanol solution (50 mL) of the free base followed by evaporation to dryness gave 4.51 g (48%) of the title compound 42 as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 11.69 (s, 1H), 7.77 (s, 2H), 6.58 (s, 1H), 2.73 (m, 2H), 2.42 (t, 2H, J=6.6 Hz), 1.76 (tt, 2H, J=7.5, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.23, 128.03, 111.69, 38.08, 25.75, 21.27; HRMS (FAB) calcd for C6H12N3S (MH+) 158.0752, found 158.0743.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[C:26]1([CH:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:34][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(N)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (±)-1-phenylethylamine (0.433 g, 3.57 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(1-phenylethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.069 g, 80.0% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])[O:13][CH:14]=1.CN(C)C1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][CH2:9][C:10]1[CH:11]=[C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])[O:13][CH:14]=1
Reactant: C[Si](C)(C)c1cc(CO)co1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: COCCOCOCc1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methoxyethoxymethyl chloride (0.11 ml, 0.96 mmol) was added to a solution of 4-hydroxymethyl-2-trimethylsilylfuran (Compound 25, also known as (2-trimethylsilyl-4-furyl)methanol, 162.8 mg, 0.96 mmol) and dimethylaniline (0 13 ml, 0.1 mmol) in dichloromethane (5 ml) at 0° After stirring at room temperature overnight (ca. 16 hours), the reaction mixture was washed successively with water, dilute hydrochloric acid and water. Evaporation of the dried (magnesium sulfate) dichloromethane layer gave an oil, which was purified by preparative silica TLC (developed with 30% ethyl ether/hexane) to give the title ether as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([OH:15])=O)[CH:6]=[CH:5][N:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH2:39])=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([O:24][C:25]([N:27]1[CH2:36][C:35]([CH3:38])([CH3:37])[C:34]2[C:29](=[CH:30][C:31]([NH:39][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][CH2:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[CH:32][CH:33]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: COc1cc(CNc2ccccc2C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNc2ccccc2C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3(C)C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-[(2-methoxy-pyridin-4-ylmethyl)-amino]-benzoic acid (Step A, 516 mg, 2.0 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol), TBTU (0.706 g, 2.2 mmol), and DIEA (0.7 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h. The mixture was diluted with more CH2Cl2. The organic layer was washed with water, brine, and dried with MgSO4. The solution was filtered, condensed, and the residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2) to obtain the titled compound as oil. MS (ES+): 517.2 (M+H)+. Calc'd for C30H36N4O4-516.27.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]I>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([NH:14][C@@H:15]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: COc1cc(C[C@H](N)C(=O)O)cc(OC)c1OC
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound is prepared by heating a suspension of 3-bromo-biphenyl (1.47 mL, 8.54 mMol, Aldrich 25,538-6), (S)-2-amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3,4,5-OCH3-phe-OH) (3.27 g, 12.81 mMol), K2CO3 (1.18 g, 8.54 mMol) and CuI (163 mg, 0.854 mMol) in DMF abs. (10.6 mL) for 24 h at 90° C., under an argon atmosphere. The resulting mixture is allowed to cool to rt, then concentrated in vacuo and purified by MPLC (CH3CN/H2O/TFA) to afford the title compound.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].C1(NN)C=CC=CC=1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C1CCCCC1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1([F:25])[CH2:24][CH:36]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCCCC1
Solvent: NNc1ccccc1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (500 mg, 1.7 mmol), and copper (II) trifluoromethanesulfonate (360 mg, 1.0 mmol) were added in an autoclave, and the mixture was cooled to a temperature below −30° C., and then 1-chloro-1-fluoroethylene (80 g, 1.0 mol) was charged under elevated pressure. Phenylhydrazine (0.11 g, 1.0 mmol) was added to this mixture under elevated pressure, and then temperature was raised to 30° C. Then, a mixed solution containing 97.6% of ethyl diazoacetate (11.69 g, 100 mmol) and cyclohexane (50 g) was charged under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to give a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (166.7 g). The content of was 3.95% (yield based on ethyl diazoacetate: 39.5%), and the ratio of cis-isomer/trans-isomer was 65.0/35.0. The optical purity of the cis-isomer was 98% e.e. (1S,2R) or more, and the optical purity of the trans-isomer was 94% e.e. (1S,2S).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[F:19][C:20]([F:30])([F:29])[C:21](OCC(F)(F)F)=[O:22]>C1COCC1>[C:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][C:21](=[O:22])[C:20]([F:30])([F:29])[F:19])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a suspension of 60% NaH (2.2 g, 55 mmol; washed with hexanes) in THF (250 mL) at 0° C. was added dropwise tert-butyl acetoacetate (8.0 g, 50.6 mmol) over a period of 15 min. The mixture was stirred for 15 min. and a homogenous solution solution resulted. A solution of 2.5M n-BuLi in hexanes (20.5 mL, 51 mmol) was added dropwise. After stirring for 15 min., 2,2,2-trifluoroethyl trifluoroacetate (11 g, 56 mmol) was added and the mixture was stirred for 30 min., quenched with HOAc, diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (anhydrous MgSO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (10:1), then hexanes:EtOAc (4:1) provided 5 g of title compound as a red-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:21]=[C:22]([CH2:26][NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:23]=[N:24][CH:25]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[CH3:31][N:30]([CH3:32])[CH2:29][CH2:28][N:27]([CH2:26][C:22]1[CH:23]=[N:24][CH:25]=[C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)[CH:21]=1)[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CN(C)CCNCc1cncc(-c2ccc3[nH]ccc3c2)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(Cc1cncc(-c2ccc3[nH]ccc3c2)c1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
4-Fluorobenzoyl chloride (111 mg, 0.7 mmol) was added to a solution of N′-[5-(1H-indol-5-yl)-pyridin-3-ylmethyl]-N,N-dimethyl-ethane-1,2-diamine (160 mg, 0.54 mmol) and triethyl amine (109 mg, 1.08 mmol) in 15 mL of dichloromethane at room temperature. The resulting mixture was stirred at ambient temperature overnight, and then a further 111 mg of 4-fluorobenzoyl chloride was added and the mixture stirred for an additional 2 h. The volatiles were removed in vacuo to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 231 mg of material. This was dissolved in dichloromethane and washed with 1M sodium hydroxide solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to leave material which was further purified by HPLC (elution with acetonitrile/water/TFA) to give 21 mg of product. LC/MS (long run): Retention time, 3.85 min; (M+H)=417.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14].CC(C)=O.[Cl-].[NH4+]>CCOC(C)=O.[Zn]>[CH3:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1Oc1c(C)cccc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(N)ccc1Oc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Zinc dust (3.86 g, 59.1 mmol) was added to a stirred solution of 4-(2,6-dimethyl-phenoxy)-3-methyl-nitrobenzene (1.5 g, 5.9 mmol), acetone (20 mL) and saturated aqueous ammonium chloride (20 mL) at 0° C. The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was diluted with 200 mL EtOAc and filtered through diatomaceous earth. The organic layer was washed with brine, dried with sodium sulfate and concentrated to provide the crude titled compound (0.79 g, 59%). This material was used without purification: MS (ESI): mass calcd. for C15H17NO, 227.3; m/z found, 227.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.07 (d, J=7.2 Hz, 2H), 7.01 (dd, J=8.3, 6.5 Hz, 1H), 6.60 (t, J=3.4 Hz, 1H), 6.31 (dd, J=8.5, 2.9 Hz, 1H), 6.06 (d, J=8.5 Hz, 1H), 3.36 (s, 2H), 2.34 (s, 3H), 2.11 (s, 6H).