Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH:16]([CH3:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:14])[C@H:11]([C:26]([O:28]C)=[O:27])[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH:16]([CH3:25])[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:14])[C@H:11]([C:26]([OH:28])=[O:27])[O:10][C:9]1([CH3:30])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC(C)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)OC(=O)[C@@H]2[C@H](C(=O)O)OC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of 2.1 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-[α-methyl-(4-methoxy)benzyloxycarbonyl]-5-oxazolidinecarboxylate in 55 cm3 of ethanol is added, at a temperature in the region of 25° C., a solution of 0.172 g of lithium hydroxide hydrate in 10 cm3 of distilled water. The reaction medium is stirred for 2 hours at a temperature in the region of 20° and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The evaporation residue is dissolved in 20 cm3 of distilled water and the solution obtained is washed with twice 15 cm3 of diethyl ether, acidified to a pH in the region of 2 by addition of aqueous 0.5N hydrochloric acid solution and extracted with twice 100 cm3 of ethyl acetate. The organic phases are combined, washed with twice 15 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.9 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-[α-methyl-(4-methoxy)benzyloxycarbonyl]-5-oxazolidinecarboxylic acid are thus obtained in the form of a white foam.
Reaction SMILES: [OH-].[Na+].C(O)C.[F:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][C:12]2[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=[CH:18][C:13]=2[C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1.Cl>C(OCC)(=O)C>[F:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][C:12]2[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:19]=[CH:18][C:13]=2[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CCCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1ccc(CCCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
10% Sodium hydroxide aqueous solution 0.2 mL was added to a suspension of ethanol 2.0 mL of methyl 2-(4-fluoroanilino)-4-(3-phenylpropyl)benzoate 0.10 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(3-phenylpropyl)benzoic acid 70 mg of white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:43])([F:44])[F:42])[CH:36]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cccc(-c2cncc(Br)c2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(C(F)(F)F)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(3-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C:17](O)=[O:18])[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.OS([O-])(=O)=O.[K+]>CCOCC.C1COCC1>[OH:18][CH2:17][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 20 mL (0.019 mol) of 1.0M LiAlH4 in Et2O was cooled to -78° C. and treated dropwise with a solution of 3.42 g (0.019 mol) of 5,6,7,8-tetrahydro-1-naphthoic acid in 20 mL THF. The solution was allowed to warm to room temperature and stirred overnight. The solution was cooled to 0° C. and decomposed with 40 mL of a 0.43M solution of KHSO4. The mixture was filtered through Celite and washed with EtOAc. The organic phase was washed with 1N HCl and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 3.02 g (98% yield) of the product. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:33])=[C:26]([F:32])[CH:27]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:19])([CH3:20])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1cc2c(cc1C)C(C(=O)OCC)=CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)c(F)c3)c(C)cc21

Procedure:
Following General Procedure B and using 6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 185, 0.2 g, 0.75 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.22 g, 0.75 mmol), triethyl amine (2 mL), copper(I)iodide (0.03 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 10–12% ethyl acetate in hexane as the eluent, the title compound was obtained as a viscous oil (0.23 g, 73%)
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[N:11](Cl)=[O:12].C(Cl)Cl>C(Cl)(Cl)Cl>[C:1]([C:3](=[N:11][OH:12])[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: O=NCl
Reactant: CC(C)(C)NC(=O)CC#N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NC(=O)C(C#N)=NO

Procedure:
2-Cyano-N-(1,1-dimethylethyl)acetamide 11 (Bhawal, B. M.; Khanapure, S. P.; Biehl, E. R.; Syn. Commun., 1990, 20, 3235) is allowed to react with nitrosyl chloride in an inert organic solvent such as CH2Cl2 or CHCl3 at moderate temperature (e.g., ambient temperature to −25° C., preferably about 0° C.). The resulting 2-cyano-N-(1,1-dimethylethyl)-2-(hydroxyimino)acetamide 13 is isolated and reduced, for example with sodium dithionite in an aqueous organic solvent, but preferably with aluminum amalgam in water at moderate temperature (e.g., ambient temperature to about 0° C., preferably about 0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:5][CH:6]([CH2:24][CH3:25])[C:7]([NH:9][C:10]([CH3:23])([CH3:22])[C:11]#[C:12][CH2:13]O[Si](C(C)(C)C)(C)C)=[O:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.[C:54](OCC)(=[O:56])C>O1CCCC1>[Cl:29][C:27]1[CH:26]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:28]=1)[O:5][CH:6]([CH2:24][CH3:25])[C:7]([NH:9][C:10]([CH3:22])([CH3:23])[C:11]#[C:12][CH2:13][CH2:54][OH:56])=[O:8]
Reactant: CCOC(C)=O
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(3,5-Dichlorophenoxy)-N-(1-tert-butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide (prepared as described in Example 1; 3.35 g) in tetrahydrofuran (60 ml) was stirred at 3-5° C. and a solution of tetra n-butylammonium fluoride (14.6 ml of 1M solution in tetrahydrofuran) was added dropwise over 5 minutes. On completion of the addition, the mixture was stirred for 0.5 hour at 0° C., 2 hours at ambient temperature and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonium chloride. The organic phase was separated, washed with aqueous ammonium chloride, brine, dried over magnesium sulphate and evaporated under reduced pressure to give a colourless solid that was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume) to give the required product as a colourless solid (2.01 g) mp 104-106° C.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1>>[CH3:12][C:7]1([CH3:13])[C:8]([CH3:11])([CH3:10])[O:9][B:5](/[CH:4]=[CH:3]/[CH2:2][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:18][CH2:19]2)[O:6]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC1(C)OB(/C=C\CCl)OC1(C)C
Product: CC(C)(C)OC(=O)NC1CCN(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Yield: 24.8 %

Procedure:
Following the procedure outlined for Example 488, (Z)-2-(3-chloroprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (210 mg, 1.1 mmol) was reacted with tert-butyl piperidin-4-ylcarbamate (640 mg, 3.2 mmol) to afford the desired product (100 mg, 30%) as a brown solid: ESI MS m/z 367 [C14H27BN2O2+H]+.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])=[CH:21][CH:22]=2)[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[CH:25][C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]([OH:7])=[O:5])=[O:42])=[CH:17]2)=[CH:22][CH:21]=1)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccc2ccc(OCC(=O)N3CCC[C@@H]3C(=O)OC(C)(C)C)cc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccc2ccc(OCC(=O)N3CCC[C@@H]3C(=O)O)cc2c1
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A solution of 272 mg (0.47 mmol) (R)-1-[[7-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 209 mg (95%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[OH:22]>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[O:22][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Oc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1c(Cl)cccc1Cl

Procedure:
A mixture of 35.0 g. of 1-benzyl-3,4-epoxypyrrolidine and 32.6 g. of 2,6-dichlorophenol was heated at 125° C. for 3 hr. The mixture was cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. The residue after the solvent was evaporated was purified by column chromatography. The product was eluted with 30% ethyl acetate in benzene and crystallized from cyclohexane. Yield was 43 g (64%) m.p. 78°-80° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C>[C:3]1([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a suspension of 2 g of 60% NaH in 50 mL of DMF cooled to 0° C. are added dropwise 5 g (42.7 mmol) of phenylacetonitrile. After stirring for 30 minutes at 0° C., 5.32 mL (42.7 mmol) of bromopentane are added dropwise. The reaction medium is stirred for 16 hours at room temperature and then treated with ice and extracted with ethyl ether. The organic phase is washed with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, filtered and evaporated under pressure. An orange-yellow oil is obtained and purified by fractional distillation under reduced pressure (70-75° C. at 1×10−1 mbar). 5.14 g in the form of an orange-coloured oil are obtained in a yield of 64%.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10](O)[C:9]1=[O:16])=[O:5].[F:17][C:18]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][NH2:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:17][C:18]([F:27])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:19][NH:20][C:10]1[C:9](=[O:16])[N:8]([CH2:7][CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:13]([CH3:14])=[CH:12][N:11]=1
Reactant: CCOC(=O)CCn1c(C)cnc(O)c1=O
Reactant: NCC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of 1-[(2-ethoxycarbonyl)ethyl]-3-bromo-6-methylpyrazinone (2-6) (0.441 g, 1.6 mmol) in toluene (15 mL) was added 2,2-difluoro-2-phenylethylamine (2-10) (0.51 g, 3.2 mmol). The resulting mixture was stirred at 110° C. for 24 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% hydrochloric acid (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/n-hexane (1:1) as eluent to afford the title compound (0.46 g, 81%) as a pale yellow solid. Rf 0.19 (ethyl acetate/hexane 1/1); 1H-NMR (CDCl3): δ 1.26 (t, J=7.2 Hz, 3H), 2.18 (d, J=1.2 Hz, 3H), 2.66 (t, J=6.8 Hz, 2H), 4.06 (dt, J=6.8, 14.4 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 4.18 (t, J=7.6 Hz, 2H), 6.11 (t, J=6.4 Hz, 1H), 6.61(d, J=0.8 Hz, 1H), 7.37-7.41 (m, 3H), 7.49-7.53 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CO.C(N(CC)CC)C.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)Cc1c(C)ncnc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate is dissolved in methanol/triethylamine (50 ml/10 ml) and hydrogenated over Pd on charcoal (0.2 g). The reaction mixture is evaporated. Addition of potassium carbonate, ether extraction and chromatography on silica gel gives pure methyl α-[6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 43.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (200 mg, 0.793 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (182 mg, 0.739 mmol), diisopropylethylamine (0.129 ml, 0.739 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration. This was recrystallized from ethyl acetate to obtain the desired product (117 mg, 43.0%) as a solid. mp 185-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.[F:21][C:22]([F:36])([F:35])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([Sn](C)(C)C)=[CH:27][N:26]=1.[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:22]([F:36])([F:21])[F:35])=[N:26][CH:27]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: C[Sn](C)(C)c1ccc(OCC(F)(F)F)nc1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccc(OCC(F)(F)F)nc3)cc2)CS1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)thiazoline (0.90 g, 2.5 mmol, obtained from precursor VP3 and Lawesson's Reagent in toluene) was mixed with 2-trifluoroethoxy-5-trimethylstannylpyridine (1.21 g, 3.6 mmol), Pd(PPh3)4 (0.15 g) and lithium chloride (0.16 g) in dioxane (10 ml) and the mixture was refluxed for 8 hours. After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-trifluoroethoxypyridin-5-yl)phenyl]thiazoline was obtained, 0.46 g, beige solid; MS: M+ 450.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=3[C:12]([O:14][CH3:15])=[O:13])=[CH:20][CH:21]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCO)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Methyl 2-{[4-(2-hydroxyethyl)phenoxy]methyl}benzoate (1 g, 3.49 mmol), 4-(benzyloxy)phenol (0.7 g, 3.49 mmol) and triphenylphosphine (1.01 g, 3.84 mmol) was added to a dry round bottomed flask fitted with a septum. N2 was flushed through the flask for 5 minutes followed by the addition of dry toluene (30 ml) and diisopropylazo-dicarboxylate (0.78 g, 3.84 mmol). The reaction mixture was stirred at 55° C. overnight. The solvent was removed by evaporation and the crude material was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). After removing the solvent by evaporation, 0.7 g of methyl 2-[(4-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoate was isolated (yield 42.8%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C1COCC1.CCCCCC>[CH2:29]([O:28][C:26]([N:12]1[C:11](=[O:13])[CH2:10][CH2:9][C@H:8]1[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 g (4 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 10 ml dry THF and cooled to −78° C. After the addition of 2.76 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 676 μl (820 mg, 4.8 mmol) benzyl chloroformate (Cbz-Cl) is added and stirring is continued at −78° C. for 2 h. The reaction is then quenched by addition of 12 ml saturated NH4Cl solution followed by 10 ml water and then extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer is dried over MgSO4, filtered and evaporated. The resulting residue (1.73 g) is purified on column chromatography (dichloromethane:methanol=99.5:0.5) to give (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (1-a, R1=Cbz) as off-white solid. NMR (400 MHz, DMSO-d6, δ/ppm): 7.66 (m, 2 H); 7.60 (m, 2H); 7.51-7.34 (m, 8 H); 7.26 (d, J=8.2, 2 H); 5.28 (s, 2 H); 4.37 (m, 1 H); 3.05 (dd, J=3.3, 13.1, 1 H); 2.88 (dd, J=9.0, 13.1, 1 H); 2.45 (m, 1 H); 2.28 (m, 1 H); 2.01 (m, 1 H); 1.77 (m, 1 H). MS (ESI, m/e) 386 [M+H]+, 788 [2M+NH4+]. IR (solution in CH2Cl2, ν/cm−1): 3092; 2957; 1756; 1705; 1488; 1396; 1304; 1287; 1231; 1139; 1043; 952; 750.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 58.2 %

Procedure:
To a mixture of 4,6-dichloropyrimidine (1.49 g, 10.0 mmol), 4-chlorophenylboronic acid (1.72 g, 11.0 mmol) and tetrakis(triphenylphosphine)palladium (1.2 g, 1.0 mmol) in toluene (20 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 10 mL, 20 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 6 h, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by trituration with MeOH (15 mL) to obtain 1.31 g of the title compound as a white solid (purity was about 80% by HPLC analysis). HPLC/MS: retention time=3.65 min, [M+H]30 =225.