Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N:11]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[C:12]=[O:13]>C1COCC1>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][NH:11][C:12]([N:2]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1]1)=[O:13]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cc1ccccc1CN=C=O
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)n1[nH]c2ccccc2c1=O

Procedure:
105 mg (0.78 mmol) of 1H-indazol-3-ol were reacted in 3 ml of THF with 138.3 mg (0.94 mmol) of 1-isocyanatomethyl-2-methylbenzene to give 3-oxo-1,3-dihydro-indazole-2-carboxylic acid 2-methylbenzylamide. 50 mg (178 μmol) of this compound were stirred in 3 ml of pyridine with 40 mg (355 μmol) of triethylamine and 43 mg (266 μmol) of 4-methylpiperidine-1-carbonyl chloride at room temperature for 7 h. Addition of a further 120 mg of 4-methylpiperidine-1-carbonyl chloride and 100 mg of triethylamine in 3 portions was followed by stirring again for 7 h, concentration and purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 48 mg (66%), M+H+: 407.15.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:36]([O:40][CH3:41])=[CH:37][CH:38]=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: COc1cccc(F)c1CBr
Product: COc1cccc(F)c1Cn1ccc2c(-c3ccc4c(c3)CCCO4)c(C(OC(C)(C)C)C(=O)O)c(C)nc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluoro-6-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.40 (m, 1 H), 7.32-7.28 (m, 1 H), 7.26-7.17 (m, 1 H), 7.04-6.99 (m, 1 H), 6.90 (dd, J=6.3, 8.3 Hz, 1 H), 6.78-6.69 (m, 2 H), 6.16-6.09 (m, 1 H), 5.62-5.55 (m, 2 H), 5.50-5.42 (m, 1 H), 4.30-4.24 (m, 2 H), 3.83 (d, J=1.8 Hz, 3 H), 2.94-2.78 (m, 2 H), 2.78-2.71 (m, 3 H), 2.07-2.03 (m, 2 H), 1.01-0.93 (s, 9 H); LC/MS (m/z) ES+=533.37 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]([C:12](=[C:15]2[NH:19][C:18]([CH2:20][CH3:21])=[CH:17][S:16]2)[C:13]#[N:14])[CH:9]=[CH:8][N:7]=1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>CC(N(C)C)=O>[C:13]([C:12](=[C:15]1[NH:19][C:18]([CH2:20][CH3:21])=[CH:17][S:16]1)[C:10]1[CH:9]=[CH:8][N:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[N:11]=1)#[N:14]
Reactant: CCC1=CSC(=C(C#N)c2ccnc(NCCCN)n2)N1
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCC1=CSC(=C(C#N)c2ccnc(NCCCNC(C)=O)n2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[(3-aminopropyl)amino]pyrimidin-4-yl}(4-ethyl-1,3-thiazol-2(3H)-ylidene)acetonitrile (165 mg, 0.37 mmol) in DMA (3 mL) were added and Et3N (0.048 mL, 0.37 mmol) and acetyl chloride (0.04 mL, 0.46 mmol) at 0° C. The resulting solution was stirred at 0° C. for 3 h. The solvent was evaporated under reduced pressure (Genevac) affording the title compound as a crude yellow solid. HPLC (max plot) 92%. The solid was taken up in DCM and an excess TFA was added. The yellow precipitate formed after addition of ether was filtered off and washed with ether (×3) then dried under vacuum at 40° C. After purification by preparative HPLC then lyophilization, 148 mg of the title compound was obtained as a TFA salt (yellow powder, Y=87.3%)
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([O:32]CC)=[O:31])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.O>[OH-].[K+].CO>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
40 mg of the ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate prepared in Example 3 was dissolved in 2 mL of 1 N KOH in methanol. 200 mL of water was then added and the mixture stirred at at 50° C. for 24 hours. The solvent was then removed and the residue dissolved in 3 mL water and brought to a pH of 3-4 by addition of 37% HCl. The resulting solid was collected by filtration and washed with water and ether then air dried to provide the product, 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].[CH3:26][N:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:7]2[CH2:8][CH2:9][N:10]([C:28]([N:27]([CH3:26])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH2:11][CH:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=1)[C:23]#[C:24][CH3:25]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N(C)c3ccccc3)CC2C(=O)OCC)cc1
Yield: 98 %

Procedure:
In the same manner as described in Step 1 of Example 215, the 1-(4but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester (1.0 g, 2.7 mmol) was treated with N-methyl-N-phenylcarbamoyl chloride to provide 1.33 g (98%) of ethyl 1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-piperazine-carboxylate as a brown oil. Electrospray Mass Spec 500.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][C:25]1[N:29]=[CH:28][NH:27][N:26]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21][S:24][C:25]3[N:29]=[CH:28][NH:27][N:26]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1nc[nH]n1
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(CSc1nc[nH]n1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 33, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 3-mercapto-1,2,4-triazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 65°-67° C., in a 91% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])[CH3:2].[Br:13]C1CC(C(C)C)CCC1=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8]([Br:13])[C:7]1=[O:12])=[O:5])[CH3:2]
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CCOC(=O)C1CCCCC1=O
Product: CCOC(=O)C1CCCC(Br)C1=O

Procedure:
The bromination of 2-oxo-cyclohexane carboxylic acid ethyl ester takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][CH2:14][CH2:15][CH2:16][OH:17]>>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]([C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: NCCCO
Reactant: O=C(O)c1cc2ccccc2s1
Product: O=C(NCCCO)c1cc2ccccc2s1
Yield: 52.3 %

Procedure:
2-Benzothiophenecarboxylic acid (5.0 g, 28.05 mmol) and 3-amino-1-propanol (2.57 ml, 33.66 mmol) were coupled according to the procedure of Example 22 to provide 3.45 g (52.3% yield) of the desired product as an orange solid. Electrospray Mass Spec: m/z 235.9 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].O[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C.C(OCC)C>[O:8]=[C:7]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[O:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C(CO)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccccc2o1
Yield: 82.9 %

Procedure:
A 2,68 M sodium ethoxide solution in ethanol (21,9 ml) was added slowly to a solution of 2-hydroxyacetophenone (1.76 ml, 14.7 mmol) and diethyl oxalate (3.98 ml, 29.4 mmol) in a mixture of dry ethyl ether (20 ml) and absolute ethanol (20 ml). The mixture was stirred under reflux for 3 h. Afterwards it was diluted with ethyl ether (40 ml), added with 1M HCl (25 ml) and extracted with ethyl ether (3×40 ml). The combined ether phases were dried and the solvents were removed by evaporation under reduced pressure. The obtained residue was dissolved in absolute ethanol (60 ml) and 0.380 ml of concentrated hydrochloric acid were added. The resulting mixture was left under stirring at 75° C. for 1 h. After this time, 50 ml of water were poured on the mixture which was extracted with ethyl acetate (3×50 ml). The organic phase was washed successively with a sodium bicarbonate saturated solution and a NaCl saturated solution, dried and the solvents were evaporated off under reduced pressure, to obtain a crude which was purified by crystallization in ethyl ether, thereby obtaining 2.660 g of the title product (83% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH3:12])[C:7]=1[C:13]#[N:14])=[O:4].[OH:16]O>>[CH3:15][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11]([CH3:12])=[O:16])[C:7]=1[C:13]#[N:14])=[O:4]
Reactant: CSc1nsc(NC(=O)N(C)C)c1C#N
Reactant: OO
Product: CN(C)C(=O)Nc1snc(S(C)=O)c1C#N

Procedure:
In the manner of Example II, 7.9 g of 1,1-dimethyl-3-(4-cyano-3-(methylthio)-5-isothiazolyl)urea was oxidized with 3.7 ml of 30% hydrogen peroxide to give 7.0 g of 1,1-dimethyl-3-(4-cyano-3-(methylsulfinyl)-5-isothiazolyl)urea, m.p. 178°-179°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:15]2[C:11]([N:12]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:14]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([C:8]1[C:15]2[C:11]([N:12]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:14]=2)=[CH:10][CH:9]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 98.2 %

Procedure:
Benzyl 4-tert-butoxycarbonyl-1-(3,4dichlorobenzyl)cyclopenta[b]pyrrole-2-carboxylate (0.7 g) was dissolved in methylene chloride (10 mL) and TFA (3 mL) was added. Stirring was continued for 24 hours and the solvents were removed in vacuo to afford a pale oil. The oil slowly solidified on standing to afford the title product (0.61 g, 98%), NMR d(DMSO) 2.40 (4H, m), 3.70 (1H, t), 5.10 (2H, s), 5.40 (2H, AB d), 6.70 (1H, s), 6.90 (1H, d), 7.30 (6H, m), 7.50 (1H, d); M/z (−) 444, 442 (M-H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1([CH2:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:9])[C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)([CH3:13])[CH3:12])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CC(C)(n1cncn1)C1(c2ccc(F)cc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(n1cncn1)C(O)(Cn1cncn1)c1ccc(F)cc1
Reaction time: 19 h
Yield: 31.9 %

Procedure:
To a solution of 2-(4-fluorophenyl)-2-[2-(1H-1,2,4-triazol-1-yl)prop-2-yl]oxirane (1.0 g, 4.0 mMole) in dimethylformamide (50 ml) were added 1,2,4-triazole (0.56 g., 8.0 mMole) and anhydrous potassium carbonate (0.56 g, 4.0 mMole). Heating at 80°, with stirring, was carried out for 19 hours. The solvent was then evaporated, water (75 ml) was added, and the mixture was extracted with methylene chloride (3×50 ml.). The combined organic extracts were washed with water (3×30 ml), dried over anhydrous magnesium sulphate, and evaporated to an impure gum (1.15 g). Purification of the gum was carried out using a flash column of Merck "Kieselgel 60" (Trademark) 230-400 mesh silica eluting with methylene chloride and 5% methanol in methylene chloride. The appropriate fractions on evaporation gave a solid which was recrystallised from diisopropylether and isopropyl alcohol giving the title compound, 0.4 g., m.p. 156°-158° (31.9% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.[ClH:19].Cl.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)[CH2:25][CH2:24]1>>[ClH:19].[ClH:19].[OH:37][CH:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH3:18])[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:28][CH2:27]2)[CH2:36][CH2:35]1
Reactant: CC(C)CCOc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: CC(C)CCOc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3-methyl-butyloxy)-1H-indole-2-carboxylic acid (84) (preparation see below) and amine 21.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH2:9]([NH:11][CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)([OH:18])[C:14]([F:17])([F:16])[F:15])[CH3:10]>>[CH2:9]([N:11]([CH2:12][C:13]([CH2:19][NH:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][N:25]2[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)([OH:18])[C:14]([F:16])([F:17])[F:15])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:10]
Reactant: O=C(O)c1cccs1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 1 from 2-thiophenecarboxylic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH2:18][CH2:19][CH3:20])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[CH:23](=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1c(OC)cc(CP(=O)(OCC)OCC)cc1OC
Reactant: COc1ccc(C=O)cc1
Product: CCCc1c(OC)cc(C=Cc2ccc(OC)cc2)cc1OC
Yield: 63 %

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-1-propylbenzyl)phosphonate and 4-anisaldehyde in 63% yield as the same procedure as described in Example 5(b). 1H NMR (CDCl3, ppm): δ 1.31 (d, J=7.1 Hz, 6H), 3.51-3.74 (m, 1H), 3.86 (s, 3H), 3.91 (s, 6H), 6.71 (s, 2H), 6.84-7.09 (m, 4H), 7.39-7.60 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC[C@H](C(=O)O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@H](C(=O)Cl)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Combine (S)-2-(4-fluorophenyl)pent-4-enoic acid (3.61 g, 18.6 mmol), dichloromethane (20 mL), and dimethylformamide (2 drops). Add oxalyl chloride (1.94 mL, 22.3 mmol). After 2 hours, evaporate in vacuo to give (S)-2-(4-fluorophenyl)pent-4-enoyl chloride. Combine with toluene (10 mL) and slowly add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (4 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, extract the organic layer with a saturated aqueous sodium bicarbonate solution. Dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-(4-fluorophenyl)pent-4-enoic acid, N-methyl amide: mp; 104-105° C. Rf =0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][CH2:2][CH:3]([C:4]([O:6][CH3:7])=[O:5])[N:8]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)C(CO)NC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 3-hydroxy-2-{[4-(trifluoromethyl)phenyl]-carbonylamino}propanoate (2.57 g, 8.83mmol) in tetrahydrofuran (30 ml) was added triphenylphosphine (2.55 g, 9.71 mmol). The mixture was cooled to 0° C., and diisopropylazodicarboxylate (1.91 ml, 9.71 mmol) was added slowly. The mixture was stirred at room temperature for 2 days. Solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography, to yield methyl 2-[4-(trifluoromethyl)phenyl]-1,3-oxazoline-4-carboxylate, a compound of formula (14). C. Preparation of a Compound of Formula (15)
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([C:5]1[O:6][C:7]2[C:13]([C@:14]([C@@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc2cc(C(C)(C)C)oc12)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
(R)-tert-butyl 3-((S)-1-(2-tert-butylbenzofuran-7-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (250 mg, 0.53 mmol) was dissolved in 20% TFA/CH2Cl2 (4 mL). The reaction mixture was stirred at rt for 1 h. The mixture was quenched with satd aq NaHCO3 (15 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4. The filtrate was evaporated to give a residue, which was purified by preparative HPLC to afford pure (S)-1-(2-tert-butylbenzofuran-7-yl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (185 mg, 94%). 1H NMR (CDCl3): 0.95 (s, 1), 1.24 (m, 2H), 1.36 (s, 9H), 1.49 (m, 3H), 1.64 (m, 2H), 2.02 (m, 2H), 2.55 (m, 2H), 2.82 (s, 1H), 3.1 (s, 1H), 3.25 (m, 5H), 3.66 (m, 1H), 6.35 (s, 1H), 7.18 (t, 1H), 7.28 (d, 1H), 7.42 (d, 1H), 8.96 (s, 1H), 9.33 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:6][C:7]=1F.[Cl:18]C1C=CC(C=O)=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:5]2[CH:4]=[CH:3][CH:2]=[C:7]([Cl:18])[N:6]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Fc1nc(NCc2ccc(Cl)cc2)ccc1Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2cccc(Cl)n2)cc1

Procedure:
To 6-chloro-pyridin-2-ylamine (537, 5.60 g, 0.0436 mol) in acetonitrile (300 mL) were added 4-chlorobenzaldehyde (40, 6.7 g, 0.048 mol), trifluoroacetic acid (13 mL, 0.17 mol) and triethylsilane (21 mL, 0.13 mol). The reaction was heated to reflux for 4 hours, then concentrated, poured into water, extracted with ethyl acetate, and washed with sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The filtrate was purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (538, 6.5 g, 59%). MS (ESI) [M+H+]+=255.1.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:31]([O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>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>[CH2:31]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C:2]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:42][CH:43]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1
Reactant: CCCCCCOc1ccc(B(O)O)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1ccc(-c2cc(C(=O)OCC)ccc2C(=O)OCC)cc1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
Diethyl bromoterephthalate (30.1 g, 100 mmol), K2CO3 (27.6 g, 200 mmol) and 140 ml of toluene and 140 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 4-hexyloxyphenylboronic acid (26.7 g, 120 mmol) (cf. B1) and Pd(PPh3)4 (1.16 g, 1 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. After 7 hours, the reaction was complete. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The product was obtained as a yellowish brown oil in sufficient purity (about 85%): 44.7 g (1112%).