Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([CH:29]([O:39]CC1C=CC(OC)=CC=1)[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][CH:33]=1)[C:22]([O:24]C(C)(C)C)=[O:23]>ClCCl>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH2:20][CH:21]([CH:29]([OH:39])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([I:38])=[CH:34][CH:33]=1)[C:22]([OH:24])=[O:23]
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(CCN1C(=O)c2ccccc2C1=O)C(O)CCc1ccc(I)cc1
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
Trifluoroacetic acid (5 mL) was added in one portion to a stirred solution of 1,1-dimethylethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate (261 mg, 0.390 mmol) in dichloromethane (5 mL) at room temperature under nitrogen. The resulting solution was stirred for 45 min then the volatiles evaporated to give the title compound (192 mg, 100%) as a yellow solid which was a mixture of diastereomers. LC/MS: 3.32 min; z/e 493, calcd (M+1) 493. 1H NMR (400 MHz: CDCl3): 7.85 (4H), 7.55 (2H), 6.95 (2H), 4.90 (1H), 3.80-3.50 (3H), 2.70-2.20 (3H), 1.85 (2H), 1.55 (2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:18])[CH:17]=1)[C:12](O)=[O:13])(=[O:8])=[O:7]>CN(C)C=O>[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:18])[CH:17]=1)[C:12]([Cl:3])=[O:13])(=[O:8])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)cc(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)cc(S(=O)(=O)Cl)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
One drop of N,N-dimethylformamide was added to a thionyl chloride (2.03 g) suspension of 3-(chlorosulfonyl)-5-fluorobenzoic acid (1.36 g), followed by stirring at 75° C. for 1 hour. The solvent was evaporated, and this was azeotroped with toluene to obtain 3-(chlorosulfonyl)-5-fluorobenzoyl chloride (1.47 g).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:2].[BH4-].[Na+].C[O-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(OC(C)C(=O)OC)c(C=O)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(OC(C)C(=O)OC)c(CO)c1
Yield: 52.1 %

Procedure:
By the method of Example 1, Step G, 49.16 grams (0.21 mole) of methyl 2-(2-formyl-4-ethylphenoxy)propionate, 2.04 grams (0.054 mole) of sodium borohydride, and 0.79 gram (0.0147 mole) of sodium methoxide were reacted in 100 mL of methanol, yielding 26.06 grams of methyl 2-(2-hydroxymethyl-4-ethylphenoxy)propionate. The NMR spectrum was consistent with the proposed spectrum.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH:14]/[N:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[CH:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1)=[S:13])([CH2:3][CH3:4])[CH3:2].C(N(CC)CC)C.Br[CH2:47][C:48](=[O:53])[C:49]([F:52])([F:51])[F:50].O>CC(=O)CC>[CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:48]([C:49]([F:52])([F:51])[F:50])([OH:53])[CH2:47][S:13]/[C:12]/1=[N:14]/[N:15]=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[CH:26][N:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:32][CH:33]=3)[N:24]=2)=[CH:19][CH:18]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1(O)C(F)(F)F
Temperature: 85 °C
Reaction time: 20 h
Yield: 6.5 %

Procedure:
To a solution of (E)-N-(2-(sec-butyl)phenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (203 mg, 0.38 mmol) in butanone (3.8 mL) was added triethylamine (0.07 mL, 0.49 mmol) and 3-bromo-1,1,1-trifluoroacetone (0.05 mL, 0.49 mmol), and the reaction was stirred at 85° C. for 20 hours, after which LC/MS analysis showed minimal conversion. Additional triethylamine (0.03 mL, 0.21 mmoL) and 3-bromo-1,1,1-trifluoroacetone (0.1 mL, 0.98 mmol) were added to the reaction mixture and the reaction was stirred at 90° C. for an additional 20 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel containing water (5 mL), and extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-20% ethyl acetate/B, where B=1:1 dichloromethane/hexanes). Further purification by reverse-phase flash chromatography (0-100% acetonitrile/water) provided the title compound as an orange solid (16 mg, 7%): 1H NMR (400 MHz, CDCl3) δ 8.59-8.54 (m, 1H), 8.30-8.13 (m, 3H), 7.79 (dd, J=8.6, 6.7 Hz, 4H), 7.45-7.34 (m, 5H), 7.32-7.21 (m, 1H), 3.99 (s, 1H), 3.83 (d, J=12.2 Hz, 1H), 3.52-3.38 (m, 1H), 2.82-2.75 (m, 1H), 1.27-1.26 (m, 1H), 1.21-1.12 (m, 3H), 0.97-0.75 (m, 4H); 19F NMR (376 MHz, CDCl3) δ −58.03, −78.23, −78.32, −78.76, −78.84; ESIMS m/z 650 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=N)[NH2:8].Cl.N[C@H](C(O)=[O:24])CCCNC(=N)N.C(OS(O)(=O)=O)CCCCCCCCCCC.N(CCO)(CCO)CCO>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:8])=[O:24]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: CCCCCCCCCCCCOS(=O)(=O)O
Agent: Cl
Solvent: OCCN(CCO)CCO
Product: NC(=O)NCCC[C@H](N)C(=O)O
Temperature: 37 °C
Reaction time: 1 h

Procedure:
[L-arginine deiminase activity is indicated in terms of micromoles of L-citrullin which are produced by reaction with L-arginine. The reaction with L-arginine is conducted by adding 10 g of the immobilized preparation to an aqueous 0.5 M L-arginine hydrochloride solution (pH 6.0) containing 0.01% of triethanolamine laurylsulfate, and shaking the mixture at 37° C. for one hour. The amount of L-citrullin produced is assayed colorimetrically by using diacetylmonooxim as a coloring agent.]
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O)[CH:23]([CH3:25])[CH3:24].[O-]CC.[Na+]>C(O)C>[CH2:22]([O:26][C:27]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=1/[CH:29]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: COc1cccc(C=O)c1OCC(C)C
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C(F)(F)F)cc2)c1OCC(C)C
Yield: 44.2 %

Procedure:
The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (400 mg, 1.922 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 285 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=3.6 Hz, 6H), 1.72 (br s, 1H), 3.58 (br s, 2H), 3.77 (s, 3H), 6.91-7.00 (m, 4H), 7.53-7.58 (m, 3H), 7.78-7.84 (m, 2H), 8.00 (br s, 1H), 8.12 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 501.24 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12].[I:14]I>FC(F)(F)S([O-])(=O)=O.[Ag+].CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:14])[C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1OC
Yield: 88.7 %

Procedure:
A methanol solution (28 ml) of 2-methoxy-4-methylbenzoic acid methyl ester (1.2 g, 7.0 mmol) obtained in Step 1 above, silver trifluoromethanesulfonate (2.0 g, 7.8 mmol), and iodine (2.0 g, 7.8 mmol) was stirred at room temperature for 1.5 hour. The reaction solution was concentrated under reduced pressure. The resulting pale yellow solid was separated by filtration, and washed with ethyl acetate (300 ml). The washing solution was sequentially washed with 5% aqueous sodium thiosulfate solution (100 ml), and a saturated aqueous sodium chloride solution (100 ml). Then, the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to yield 5-iodo-2-methoxy-4-methylbenzoic acid methyl ester (1.9 g) as a pale yellow solid material.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[N:19]=[C:20]([NH2:22])[N:21]=[C:17]3[CH:16]=[CH:15][N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1CCOCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[N:19]=[C:20]([NH:22][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:36][CH:37]=4)[N:21]=[C:17]3[CH:16]=[CH:15][N:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Reactant: Nc1nc2ccnc(-c3cnn(Cc4ccccc4)c3)n2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: c1ccc(Cn2cc(-c3nccc4nc(Nc5ccc(OCCN6CCCC6)cc5)nn34)cn2)cc1
Temperature: 130 °C

Procedure:
In a microwave vial, 5-(1-benzyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.05 g, 0.165 mmol), 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (0.045 g, 0.215 mmol), bis(dibenzylideneacetone)palladium (0.005 g, 0.008 mmol), xantphos (0.01 g, 0.017 mmol) and sodium tert butoxide (0.032 g, 0.330 mmol) were added successively. 1,4-Dioxane (1.2 mL) and dimethylacetamide (4 drops) were added and the vial was sealed and heated in the microwave (130° C., 15 min). The mixture was filtered and purified by preparatory HPLC. LCMS method: 2, RT: 2.54 min; MI: 481 [M+1]. 1H NMR (DMSO) 9.70 (s, 1H), 8.92 (s, 1H), 8.49 (s, 1H), 8.20 (d, 2H), 7.54 (d, 2H), 7.32 (m, 3H), 6.92 (d, 2H), 5.50 (s, 2H), 4.09 (t, 2H), 2.78 (t, 2H), 2.52 (s, 4H), 1.64 (s, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])[CH:5]=[C:6]([F:12])[C:7]=1[S:8]([CH3:11])(=O)=O.[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>C(OC(=O)C)(=O)C>[C:25]([O:28][CH2:11][S:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[CH:5][C:6]=1[F:12])(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(C)(=O)=O)c(F)c1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCSc1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Yield: 82.3 %

Procedure:
A slurry of 4-[3,5-difluoro-4-(methylsulfinyl)phenyl]-5-methyl-3-phenylisoxazole (2.3 g, 6.8 mmol)(step 9 example 14), sodium acetate (3.4 g, 41 mmol) in acetic anhydride (30 mL) was heated and held at reflux for 9 hours. The mixture was concentrated on at reduced pressure and the residue was treated with dilute aqueous sodium bicarbonate and extracted with dichloromethane (1×200 mL, 2×75 mL). The combined extracts were washed with dilute sodium bicarbonate, dilute ammonium chloride, dried with magnesium sulfate and concentrated. The product was purified by silica gel chromatography using 1% ethyl acetate/50% dichloromethane in hexanes to give {[2,6-difluoro-4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]thio}methyl acetate as a white solid (2.1 g, 82%), MP 130.3-130.3° C. 1HNMR (CDCl3/400 MHz) 7.34-7.43 (m, 5H), 6.73-6.79 (m, 2H), 5.29 (s, 2H), 2.49 (s, 3H) 2.05 (s, 3H). HRMS m/z 376.0822 (M+H+, Calcd 376.0819). Anal. Calcd for C19H15F2NO3S: C, 60.79; H, 4.03; N, 3.73; Found: C, 60.44; H, 4.09, N 3.66.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>N1C=CC=CC=1>[C:15]([O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)NC1CCC(O)c2sccc21
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)NC1CCC(OC(=O)c2ccccc2)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of pyridine, 0.53 g of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylurea is stirred and 0.39 g of benzoyl chloride added under a nitrogen atmosphere. The mixture is stirred at room temperature and after 1 hr, an additional 0.2 g of benzoyl chloride is added. After another 0.75 hr, the mixture is poured into H2O and the white precipitate is collected. The solid is washed with H2O, dried, dissolved in acetone-hexane and filtered to remove an insoluble material. The filtrate is evaporated to dryness and the acetone-hexane treatments are repeated twice to remove additional side product. The solid from the filtrate is recrystallized from ethyl acetate to give a solid with m.p. 199° C-205° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:26][CH3:27])[C:5]([N:8]([C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2I)(=[O:11])=[O:10])=[N:6][CH:7]=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[N:3]=[C:4]([O:26][CH3:27])[C:5]([N:8]([C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[S:9]([C:12]2[C:13]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH:29]4[CH2:30][CH2:31][CH2:32][CH2:33][O:28]4)=[CH:36][CH:37]=3)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(OC2CCCCO2)cc1
Reactant: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1I
Product: COc1nc(Cl)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1ccccc1-c1ccc(OC2CCCCO2)cc1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in Example 1 part (v), but starting from N-(5-chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-2-iodobenzenesulphonamide and 4-(2-(2H)-tetrahydropyranyloxy)phenylboronic acid, there was obtained in 57% yield N-(5-chloro-3-methoxypyrazin-2-yl)- N-(isobutoxycarbonyl)-4'-[2-(2 H)-tetrahydropyranyloxy]-2-biphenylsulphonamide, m.p. 142°-143° C.; microanalysis found: C, 56.3; H, 5.5; N, 7.1%; C27H30C1N3O7 requires: C, 56.3; H, 5.25; N, 7.3%.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:47]([NH:51][CH2:52][C:53]1[CH:64]=[CH:63][C:56]([O:57][CH2:58][C:59]([O:61][CH3:62])=[O:60])=[C:55]([CH3:65])[CH:54]=1)[CH2:48][CH2:49][CH3:50].Br[C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([C:73]2[CH:78]=[CH:77][C:76]([C:79]([F:82])([F:81])[F:80])=[CH:75][CH:74]=2)[N:68]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:47]([N:51]([CH2:52][C:53]1[CH:64]=[CH:63][C:56]([O:57][CH2:58][C:59]([O:61][CH3:62])=[O:60])=[C:55]([CH3:65])[CH:54]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([C:73]2[CH:78]=[CH:77][C:76]([C:79]([F:80])([F:82])[F:81])=[CH:75][CH:74]=2)[N:68]=1)[CH2:48][CH2:49][CH3:50]
Reactant: CCCCNCc1ccc(OCC(=O)OC)c(C)c1
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccc(OCC(=O)OC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Yield: 34.3 %

Procedure:
Palladium (II) acetate (5.4 mg, 0.024 mmol) and (S)-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (22 mg, 0.036 mmol) in anhydrous toluene (1.2 mL) were stirred together at 70° C. in a sealed reactivial for 30 minutes. The vial was then allowed to attain room temperature before the methyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (96 mg, 0.36 mmol), 2-bromo-6-[4-(trifluoromethyl)phenyl]pyridine (90.6 mg, 0.3 mmol) and caesium carbonate (137 mg, 0.42 mmol) were added. The vial was then sealed and heated at 80° C. for 18 h. The reaction mixture was allowed to cool to room temperature, the reaction mixture filtered and the solvent removed in vacuo. Purification by SPE (Silica, 10 g) eluting 99:1–50:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (50 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([NH:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([NH:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NCCCc2ccccc2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(NCCCc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
1.0 mL of trifluoroacetic acid solution containing 0.11 g of tert-butyl 2-(benzamido)-4-((3-phenylpropyl)amino)benzoate was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and ethyl acetate and water were added and pH was adjusted to pH 6.3 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure, Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 71 mg of 2-(benzamido)-4-((3-phenylpropyl)amino)benzoic acid as white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1)[CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]([CH3:6])[CH2:4][CH2:3][OH:2])=[CH:8][C:9]=1[C:14]([F:15])([F:16])[F:17]
Reactant: COC(=O)CN(C)c1ccc(Br)c(C(F)(F)F)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(CCO)c1ccc(Br)c(C(F)(F)F)c1
Reaction time: 14 h
Yield: 81.8 %

Procedure:
A solution of [(4-bromo-3-trifluoromethyl-phenyl)-methyl-amino]-acetic acid methyl ester (77.6 mg, 0.238 mmol) in THF (1.0 ml) was added dropwise to a suspension of lithium aluminum hydride (372 mg, 2.58 mmol) in THF (1.5 ml) at 0° C. The mixture was stirred for 14 hours while gradually warming from 0° C. to room temperature. A 2 N aqueous HCl solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 2-[(4-bromo-3-trifluoromethyl-phenyl)-methyl-amino]-ethanol (58.0 mg, 82%).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([CH2:18][C:19]([OH:21])=O)([C:15]([OH:17])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2([C:15](=[O:17])[N:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:19](=[O:21])[CH2:18]2)[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)CC1(C(=O)O)CCN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a solution of (1-benzyl-4-carboxypiperidin-4-yl)acetic acid.hydrochloride (31.3 g) in dimethylformamide (200 ml) was added dicyclohexylcarbodiimide (20.6 g). The mixture was stirred for one hour at room temperature, to which were added benzyloxyamine hydrochloride (16 g) and triethylamine (14 ml). The mixture was stirred for further one hour at room temperature, followed by evaporating off the solvent under reduced pressure. To the residue were added acetic anhydride (150 ml) and sodium acetic anhydride (21 g). The mixture was stirred for one hour at 100° C., then insolubles were filtered off, and the solvent was evaporated off under reduced pressure. To the residue was added ethyl acetate (200 ml), to which was further added a saturated aqueous solution of sodium hydrogencarbonate until the aqueous layer became alkaline. The organic layer was washed with water, dried over anhydrous magnesium sulfate, followed by evaporating off the solvent under reduced pressure. To the residual oil was added 100 ml of acetonitrile, and insolubles were filtered off. Acetonitrile was evaporated off, and the residue was recrystallized from acetonitrile-ethyl ether to obtain 16.5 g of a colorless solid, m.p. 146° to 152° C.
Reaction SMILES: Cl[C:2]([O:5]C(Cl)=O)(Cl)Cl.CO[N:11]([C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[N:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([O:15]CC)=O>O1CCCC1>[CH3:2][O:5][C:30]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:24]1[O:31][C:13](=[O:15])[N:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)N(c1ccccc1)N(OC)C(=O)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(-c2ccccc2)c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,2 ml of trichloromethylchloroformate (diphosgene) are added, with stirring, to a solution of 6,3 g of ethyl N′-methoxybenzoyl-N-phenyl-hydrazine-carboxylate in anhydrous tetrahydrofuran at ambient temperature. After one hour's stirring at ambient temperature the solvent is distilled off in vacuo and the residue remaining is recrystallised from ethanol. Yield: 6.5 g (96%), melting point: 112-115° C.