Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1[O:18][CH3:19].C[O:21][B:22](OC)[O:23]C.Cl>O1CCCC1.O>[CH3:19][O:18][C:8]1[CH:9]=[CH:10][C:11]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=1[B:22]([OH:23])[OH:21]
Reactant: COc1ccc(OC(F)(F)F)cc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.6M in hexanes, 3.8 mL, 6 mmol) was added dropwise to a cooled (−78° C.) solution of 2-bromo-1-methoxy-4-(trifluoromethoxy)benzene (Description 16, 1.5 g, 5.5 mmol) in tetrahydrofuran (prefiltered through alumina, 18 mL) [internal temperature <−70° C.]. The mixture was stirred at −78° C. for 15 min., then trimethylborate (2 mL, 17.6 mmol) was added dropwise [internal temperature <−70° C.]. The mixture was stirred at −78° C. for 30 min., then hydrochloric acid (1M, 6 mL) was added. The mixture was warmed to room temperature and stirred for 30 min. Water (25 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The combined organic fractions were washed with water (20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo at 40° C. to give the title compound as an off white solid (366 mg, 28%). 1H NMR (360 MHz, CDCl3) δ3.93 (3H, s), 5.84 (2H, s), 6.90 (1H, d, J 9.0 Hz), 7.29 (1H, m) and 7.70 (1H, J 2.6 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.C(OO)(=[O:18])C.S(=O)(=O)(O)O.[OH-].[Na+]>CC(C)=O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:13]([OH:18])=[N:12][CH:11]=[N:10][CH:9]=1
Reactant: CC(=O)OO
Reactant: N#Cc1nccc(-c2cncnc2)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: N#Cc1nccc(-c2cncnc2O)c1F
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a vial charged with 3-fluoro-4-(pyrimidin-5-yl)picolinonitrile (0.400 g, 1.998 mmol) in acetone (Volume: 11.89 ml) were added peroxyacetic acid (0.841 ml, 4.00 mmol) and sulfuric acid (0.222 ml, 4.00 mmol). The reaction mixture was refluxed for 1 h, and then allowed to cool to room temperature. The reaction mixture was neutralized with 4 M NaOH and extracted with CH2Cl2 (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 40 mL/min, 0-25% MeOH in CH2Cl2 over 25 min, tr=16 min) gave the title compound (263 mg, 1.204 mmol, 60.3% yield) as a yellow solid. ESI MS (M+H)+=217.1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[C:1]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(CCO)CC1
Reaction time: 16 h
Yield: 93.6 %

Procedure:
Benzoyl chloride (13.3 mL, 0.115 mole) was added dropwise over 0.5 hour to a 0° C. solution of 4-piperidineethanol (14.8 g, 0.115 mole) and dry triethylamine (18 mL, 0.13 mole) in dichloromethane with mechanical stirring. After 16 hours at room temperature, the mixture was quenched with 1.0 M aqueous NaOH (150 mL), then extracted with ethyl acetate (1 L). The organic phase was extracted further with H2O (125 mL), then brine (125 mL), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel, eluting with chloroform to 6% methanol in chloroform, followed by concentration in vacuo and drying at 100° C. under high vacuum for 1.5 hour to yield a viscous oil (25.1 g, 94%). IR (neat): 3409 cm-1 (s,br), 1613(s). HRMS: Calculated for C14H19NO2 : 233.1416; found: 233.1410.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18]C)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([OH:18])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
To a solution of methyl 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoate (2.260 g, 6.29 mmol) in THF (25 ml), aqueous 1M LiOH (6.29 ml, 6.29 mmol) was added, and the reaction was stirred at RT for 6 hours. Additional 1M LiOH (12.58 ml, 12.58 mmol) was added over 3 days with stirring at the same temperature. The solvents were removed under vacuum, and the residue was partitioned between EtOAc and 2N HCl; the organic phase was dried over Na2SO4 and the solvent was removed. The crude was purified by chromatography on silica gel column (DCM:MeOH=98:2 to 9:1) to afford 3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoic acid (1.240 g, 3.59 mmol, 57.1% yield, MS/ESI+ 368.0 [MHNa]+).
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]#[C:3][C:4]([O:6][CH3:7])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:12]1([NH:11]/[C:3](=[CH:2]/[C:1]([O:9][CH3:10])=[O:8])/[C:4]([O:6][CH3:7])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1
Solvent: CO
Product: COC(=O)/C=C(/Nc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl but-2-ynedioate (1.452 mL) in methanol (20 mL) was added aniline (0.98 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was purified by column chromatography on silica gel (20-50% ethyl acetate in hexane) to obtain the title compound (1.73 g) having the following physical data.
Reaction SMILES: N1([C:6]([CH3:16])=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)CCCC1.[NH2:17][C:18]1[C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][NH:20][N:19]=1>C(O)(=O)C>[CH3:16][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:19]2[N:20]=[CH:21][C:22]([C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])=[C:18]2[N:17]=1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Reactant: CC(=CC(=O)c1ccncc1)N1CCCC1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccncc2)n2ncc(C(=O)c3ccccc3)c2n1

Procedure:
A mixture of 0.05 mole of 3-(1-pyrrolidinyl)-1-(4-pyridinyl)-2-buten-1-one and 0.05 ml of (3-amino-1H-pyrazol-4-yl)phenyl-methanone in 50 ml of glacial acetic acid was refluxed for 8 hours. The solvent was removed and the residue partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was washed with water, dried over magnesium sulfate and passed through a short pad of hydrous magnesium silicate. The eluent was concentrated and the residue crystallized from dichloromethane:hexane, giving the desired product, mp 209°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27]>>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:7])=[CH:24][CH:25]=1)[CH3:27]
Reactant: Cc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccc(C)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 3-(4-hydroxybenzoyl)-2-(4-tolyl)benzofuran with 3-diethylaminopropyl chloride by the procedure described in Example 1 gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:14]([CH3:20])=[N:15][N:16]([CH3:19])[C:17]=1[CH3:18])=[S:11]
Reactant: Cc1nn(C)c(C)c1N
Reactant: Cc1cccc(Cl)c1N=C=S
Product: Cc1cccc(Cl)c1NC(=S)Nc1c(C)nn(C)c1C
Yield: 66.8 %

Procedure:
Prepared using Method A from 4.0 g (21.8 mmol) of 2-chloro-6-methyl-phenyl isothiocyanate and 2.7 g (21.8 mmol) of 4-amino-1,3,5-trimethylpyrazole to give 4.5 g of title compound as a white solid (67% yield, m.p. 201-202° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:28])[CH:5]([O:25][CH2:26][CH3:27])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)OCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 73.9 %

Procedure:
The compound obtained in Step b (53.7 mg) was dissolved in trifluoroacetic acid (2 ml), added with triethylsilane (0.4 ml, Aldrich) and stirred at room temperature for 2.5 days. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over magnesium sulfate and concentrated. The resulting residue was applied on a silica gel column and eluted with chloroform/methanol (10:1) to obtain the title compound (28.1 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C)C=O.O>[CH:11]1([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OC2CCCC2)cc1
Reaction time: 0.33 h

Procedure:
Sodium hydride (50% in oil; 4.8 g) was added in portions to a solution of 4-aminophenol (10.9 g) in dimethylformamide (150 ml). After 20 minutes, cyclopentyl bromide (14.9 g) was added dropwise. After 2 hours at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 3:1). The product with the molecular weight of 177.25 (C11H15NO); MS (ESI): 178 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:12](OCC)[O:13]CC)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:12]=[O:13])=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCOC(OCC)c1cc(CC)c(C(=O)OC)s1
Solvent: C1COCCO1
Solvent: O=CO
Product: CCc1cc(C=O)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
A solution of 5-Diethoxymethyl-3-ethyl-thiophene-2-carboxylic acid methyl ester (1.76 g, 6.46 mmol) in dioxane (16 ml) was cooled to 0° C. (ice bath). 88% formic acid (20 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 90 min. The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (1.22 g, 95% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:24](=[O:33])[N:25]([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C=1>>[CH:11]1([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:24](=[O:33])[N:25]([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:7][CH:6]=2)=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(Nc1ccc(O)cc1)C1CCCCC1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)C2CCCCC2)cc1)c1ccccc1
Yield: 80.3 %

Procedure:
The title compound (283 mg, 80% yield, white crystals) was prepared from cyclohexanecarboxylic acid (4-hydroxyphenyl) amide (219 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=353 (M+1); Rt=4.23 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19](O)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].[N:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:38]=3)[N:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:12][CH2:13][CH:14]([O:17][CH2:18][C:19]([N:29]3[CH2:30][CH2:31][N:26]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:42]([F:45])([F:43])[F:44])[CH:38]=5)[N:33]=4)[CH2:27][CH2:28]3)=[O:20])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:22]([F:23])([F:24])[F:25])([O-:3])=[O:2]
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: FC(F)(F)c1ccc2nc(N3CCNCC3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc3cc(C(F)(F)F)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added 2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline (93.1 mg, 0.33 mmol, 1.2 eq), EDAC.HCl (79 mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), Et3N (84 mg, 0.83 mmol, 3 eq). The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 ml), extracted with of dichloromethane (3×30 ml) and the organic layers were combined and dried over anhydrous sodium sulfate. The organic solution was filtered and then concentrated under vacuum. The crude material was purified by Pre-TLC using 4% methanol in dichloromethane to elute. Concentration of the product-containing fractions afforded 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one as a yellow solid (77 mg, 45%). (ES, m/z): [M+H]+ 626.40. 1H NMR (300 MHz, CD3OD): δ 8.13 (d, J=9.0 Hz, 1H), 8.02-8.05 (t, J=4.5 Hz, 2H), 7.42-7.79 (m, 2H), 7.29 (d, J=9.3 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.78-6.81 (dd, J=2.4, 9.2 Hz, 1H), 4.34 (s, 2H), 3.88-3.94 (m, 4H), 3.72-3.78 (m, 4H), 3.45-3.50 (m, 2H), 2.10-2.20 (m, 4H), 1.34-1.54 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH2:42][CH:43]([CH3:44])[CH3:45])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (218 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as an off-white solid (320 mg, 77%).
Reaction SMILES: [CH2:1](N)[CH2:2]CC.[C:6]([N:13]1[CH:17]=[CH:16]N=[CH:14]1)([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:7].O>C1COCC1>[CH2:17]([N:13]([CH3:14])[C:6]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)=[O:7])[CH2:16][CH2:1][CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCN
Solvent: O
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)n1ccnc1

Procedure:
Butylamine (20 g, 0.23 mol) was dissolved in 100 mL of THF and added at a quick dropwise rate to a suspension of carbonyldiimidazole (37.2 g, 0.23 mol) in 200 mL of THF. The solution was headed to reflux for 3 h, then cooled, treated with 200 mL of water, and partitioned into ethyl acetate. The organic layer was separated and then washed with brine, dried with MgSO4, and then concentrated to the crude imidazolide, which was purified by distillation at 108° C. and 600 mtorr to provide a pure oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 3.40 (t, J=7.60 Hz, 2H), 3.06 (s, 3H), 1.61 (m, 2H), 1.31 (m, 2H), 0.93 (t, J=7.23 Hz, 3H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:23].Cl>C1C=CC=CC=1>[CH3:10][C:11]12[C:12](=[O:23])[CH:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][C:20]=31)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Reactant: BrCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C1(C)CCCCCC(C2)C1=O
Reaction time: 12 h

Procedure:
Oil-free sodium hydride (5.28 g.) in benzene (50 ml.) is added to a stirred mixture of 1,5-dibromopentane (184 g.) and 1-methyl-7-methoxy-2-tetralone (32 g.) in dry benzene (300 ml.). Stirring is continued for 12 hours at 25° and at reflux for an additional 15 hours. The mixture is cooled, sodium hydride (5.8 g.) in 50 ml. benzene added, stirring continued at 25° for 10 hours, and at reflux for 12 additional hours. After cooling excess base is neutralized with concentrated hydrochloric acid and the inorganic solids which precipitate are removed by filtration. Washing and filtrate with saline, drying over sodium sulfate, concentrating and vacuum distilling gives an oil (21 g.), b.p. 160°-190° C. (0.5 mm.) containing 6.5 g. (27 percent) of the title product by vapor phase chromatographed (3 percent OVI, C200- 225- 250).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[O:20][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOCn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Reactant: O=C(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1nccc1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Yield: 56.3 %

Procedure:
0.63 g of 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol, 0.58 g of bromoacetic acid and 1.11 g of potassium carbonate are added to 40 ml of acetone, and the mixture is refluxed for 48 hours. The reaction mixture is concentrated to remove solvent, and water is added to the residue. The aqueous mixture is washed with ethyl acetate, acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is crystallized with water, and the crystals are separated by filtration, washed successively with water and isopropyl ether, and dried to give 0.42 g of [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:10]=1.[OH-].[Na+].C(OCC)(=O)C>C(#N)C>[Br:1][C:14]1[N:9]=[CH:10][C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccnc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
2.70 g (15.19 mmol) of N-bromosuccinimide (NBS) are added portionwise to a solution of 4 g (15.19 mmol) of 1,1-dimethylethyl 4-(3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.1., in 50 ml of acetonitrile, cooled to about 0° C. Stirring is continued at 0° C. for 15 minutes and then at room temperature for 2 hours. 100 ml of aqueous sodium hydroxide solution (1M) and 100 ml of ethyl acetate are added to the reaction medium. The aqueous phase is separated out and extracted twice with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. 5.16 g of product are thus obtained in the form of an orange-yellow solid, and are used without further purification in the following step.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:12][CH:11]([CH2:13][O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4]1)(=[O:25])=[O:24]
Reactant: OCC1CC(CO)CC2(C1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)CC2(C1)OCCO2
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 7,9-bis(hydroxymethyl)-1,4-dioxaspiro[4.5]decane (6.3 g, 21 mmol) in dry dichloromethane (100 ml) with triethylamine (8.90 ml, 63.8 mmol) was added methanesulfonyl chloride (4.11 ml, 53.2 mmol) drop-wise at 0° C. The reaction was allowed to come to ambient temperature and stir overnight. The reaction was quenched with saturated sodium bicarbonate (50 ml) and allowed to stir for 15 min. After separation, the aqueous layer was extracted with dichloromethane (1×50 ml). The combined extracts were dried over potassium carbonate, filtered and concentrated to give a dark brown liquid (7.3 g, 97%).
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:14]([O:13][C:11](=[O:12])[C:10]([S:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:17])[CH3:16])[CH3:15]
Reactant: SC1CCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCCC1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
To a solution of 5 g (48.7 mmol) of cyclopentyl thiol in ethanol (50 mL) are added 2.7 g (48.75 mmol) of KOH pellets, followed by 9.5 g (48.7 mmol) of ethyl α-bromoisobutyrate. The reaction is heated to reflux for 2 h and then cooled to room temperature. The solid (KBr) is separated by filtration and rinsed with ethanol (20 mL). The filtrate is concentrated under reduced pressure and the residue dissolved in DCM (50 mL). The organic layer is washed with saturated aqueous NaHCO3 solution (50 mL). The aqueous washes are back-extracted with DCM (10 mL). The combined organics are washed with brine, dried over Na2SO4. Filtration and concentration under reduced pressure affords 8.1 g of 2-cyclopentylsulfanyl-2-methyl-propionic acid ethyl ester. Yield: 77%, ES-MS: m/z 217 [M+H]