Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:10]=[CH:9]2)([O-])=O>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:10]=[CH:9]2
Reactant: CC(C)(C)OC(=O)n1ncc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cccc(N)c21
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of 7-Nitro-1-tert-butoxycarbonyl-indazole (1.000 g, 3.798 mmol), prepared as in Intermediate 25, and palladium on carbon (10 wt %, 0.10 g) in ethyl acetate (25 mL) at ambient temperature is stirred under atmospheric hydrogen overnight. The mixture is filtered through celite and concentrated in vacuo to an oil which solidified under high vacuum to provide the title compound as a purple solid (0.860 g, 3.686 mmol). 1H NMR (300 MHz, d6-DMSO) δ=1.59 (b, 9H); 6.13 (b, 2H); 6.76 (d, J=7.6 Hz, 1H); 6.97 (d, J=7.6 Hz, 1H); 7.04-7.07 (m, 1H); 8.24 (s, 1H). TLC: Rf =0.47 (25:75 ethyl acetate: n-hexane).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[N:17]([CH3:20])[CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:22]([O-])=O.CCO.O.C(=O)(O)[O-].[Na+]>Cl.[Fe].CCOC(C)=O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:21])[N:17]([CH3:20])[CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:22]
Reactant: CCN(C)C(=O)c1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2F)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCN(C)C(=O)c1ccc(Sc2ccc(N)c(Cl)c2F)cc1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
2-Chloro-3-fluoro-4-[4-(N-methyl-N-ethylcarbamoyl)phenylsulphanyl]nitrobenzene (Method 81; 650 mg. 1.76 mmol) was heated with stirring at 75° C. for 45 minutes with of iron powder (1.06 g), EtOH (1.2 ml), water (0.5 ml) and 2 drops of conc. HCl. The mixture was then allowed to cool to room temp, made basic with saturated sodium bicarbonate solution, and EtOAc was added. The reaction mixture was filtered through a bed of diatomaceous earth, washing through thoroughly with water and EtOAc. The organic layers were combined and washed with water, dried, filtered and evaporated to dryness to give the title compound (600 mg) as a pale yellow gum. NMR: 1.0 (s, 3H), 2.8 (s, 3H), 3.2 (d, 2H), 6.2 (s, 1H), 7.0 (m, 2H), 7.2 (m, 3H).
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:13])[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:26])[F:27])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:10][CH:11]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN(c1ccc(O)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
13.8 g (40 mmol) of 4-methylaminophenol hemisulfate (twice suspended in toluene and evaporated under reduced pressure to remove water) were suspended in 100 ml hexamethyldisilazane and refluxed for 2.5 h. The solution was evaporated under reduced pressure and dissolved in 270 ml THF. 9.79 g (40 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride were added slowly at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 30 ml H2O were added and after 1 h the solvents were evaporated. The residue was extracted with water/Et2O (3×), the organic phases were washed with 10% NaCl, dried (Na2SO4) and evaporated to yield 13.3 g (100%) of N-(4-hydroxy-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, mp: 145-146° C.; MS: 331 (M).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=4[N:25]=[CH:26][N:27]=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:44][CH:43]=1)[C:15](=[O:32])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]3[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=3[N:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)cc3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N(CCN)Cc4ccc(Cl)cc4)cc3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
TFA (182 μL, 2.36 mmol) was added to a solution of (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamido)ethylcarbamate (49 mg, 0.094 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC to give (R)-N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide as an oil (9 mg, 22%). MS (APCI+) [M+H]+ 421.2. 1H NMR (D2O, 500 MHz) δ 9.09 (s, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.15 (D, J=8.0 Hz, 2H), 4.63 (s, 2H), 3.87 (t, J=6.5 Hz, 2H), 3.82-3.79 (m, 1H), 3.26-3.11 (m, 4H), 2.63 (s, 2H), 2.50-2.42 (m, 1H), 1.86-1.81 (m, 1H), 0.86 (s, J=7.00 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]=[CH2:22]>C(#N)C>[CH2:22]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH2:21][CH:20]=[CH2:19]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCOc1ccc([N+](=O)[O-])cc1F

Procedure:
To an acetonitrile (40 mL) solution of 2-fluoro-4-nitrophenol (2.36 g; 15.1 mmol) and potassium carbonate (2.77 g; 20.1 mmol), 4-bromo-1-butene (2.81 g; 20.4 mmol) was added, and the mixture was refluxed and then reacted for 16 hours. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(3-butenyloxy)-3-fluoronitrobenzene (1d) (2.57 g, 81% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:39]([O:41]C)=[O:40])=[C:11]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[S:43]([CH2:46][CH3:47])(=[O:45])=[O:44])[CH3:4]>CO.O>[CH2:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:39]([OH:41])=[O:40])=[C:11]([CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:31][CH2:32]3)[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[S:43]([CH2:46][CH3:47])(=[O:45])=[O:44])[CH3:4]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(=O)(=O)CC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(=O)(=O)CC
Temperature: 25 °C
Yield: 88.9 %

Procedure:
Potassium hydroxide (1.805 g, 32.2 mmol) was added to a solution of methyl 7-(ethyloxy)-6-(ethylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.09 g, 3.22 mmol) in methanol (60 mL) and water (20 mL). The mixture was heated to reflux overnight, cooled to room temperature, and diluted with water. The methanol was removed under reduced pressure, and the remaining aqueous solution was acidified to pH 6 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo to afford 7-(ethyloxy)-6-(ethylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.82 g, 89% yield). 1H NMR (400 MHz, DMSO-d6) ™ 8.80 (s, 1H), 8.03 (s, 1H), 7.88-7.94 (m, 2H), 7.76-7.82 (m, 1H), 7.67 (s, 1H), 4.37 (q, J=6.94 Hz, 2H), 4.08 (br. s., 2H), 3.50-3.62 (m, 6H), 2.99 (br. s., 2H), 2.31-2.59 (m, 6H), 1.79 (d, J=12.30 Hz, 2H), 1.45 (t, J=6.90 Hz, 3H), 1.23-1.41 (m, 3H), 1.14 (t, J=7.40 Hz, 3H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:40])[CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[NH2:32][CH2:31][CH2:30][C:29]([NH:28][CH2:27][CH2:26][CH2:25][N:24]([S:41]([CH3:44])(=[O:42])=[O:43])[C:12]1[C:13]([CH:21]2[CH2:22][CH2:23]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]=2[C:17]([NH:18][CH3:19])=[O:20])=[O:40]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCNC(=O)CCNC(=O)OC(C)(C)C)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCNC(=O)CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A mixture of compound (ii) (20 mg, 0.029 mmol) and trifluoroacetic acid (50 uL) in DCM (0.5 mL) was stirred at 40° C. for 1 h. After cooling to RT, solid potassium carbonate (50 mg) was added and the mixture was stirred vigorously for 10 min. Water (0.5 mL) was then added and the organic phase was separated. The aqueous phase was extracted with DCM (1 mL) and the combined organics were dried (MgSO4) then concentrated in vacuo. The residue was purified by flash column chromatography eluting with MeOH/DCM (0-20%) to afford Compound (61) as a white solid (5.4 mg, 32%). ESI-MS m/z calculated for [M+H]+: 591.1/593.1; found: 591.1/593.1; 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.69-7.60 (m, 2H), 7.50-7.42 (m, 2H), 7.35 (s, 1H), 7.24 (t, J=4.3 Hz, 1H), 5.95 (brd, J=4.6 Hz, 1H), 3.92-3.68 (m, 2H), 3.46-3.22 (m, 2H), 3.06 (s, 3H), 3.02-2.90 (m, 5H), 2.38 (tt, J=8.4, 5.4 Hz, 1H), 2.31-2.16 (m, 2H), 1.92-1.68 (m, 2H), 1.12-0.96 (m, 3H), 0.67-0.54 (m, 1H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)[CH2:21][CH3:22]>>[CH2:20]([C:23]1[N:24]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:25]=[CH:26][N:27]=1)[CH2:21][CH3:22]
Reactant: CCCc1ncc[nH]1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Product: CCCc1nccn1-c1cc2c(cc1[N+](=O)[O-])[nH]c(=O)c1n[nH]c(=O)n12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and 2-n-propylimidazole by a method analogous to the method described in example 11. M.p. 260° C. decomp.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[C:8]([F:10])[CH:9]=1.ClCCl.[Br:15][CH2:16][CH2:17]Br>O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Br:15][CH2:16][CH2:17][S:11][C:6]1[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: Fc1cc(F)cc(S)c1
Reactant: BrCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(F)cc(SCCBr)c1

Procedure:
A solution of 2.59 g of sodium hydroxide pellets in 27 cm3 of distilled water and then 0.27 cm3 of aliquat 336 (tricaprylylmethylammonium chloride) were added, with stirring and under an inert atmosphere, to a mixture, maintained at a temperature in the region of 23° C., of 7.5 g of 3,5-difluorothiophenol in 9.01 cm3 of 1,2-dibromoethane. After stirring for 15 minutes at a temperature in the region of 20° C., 50 cm3 of dichloromethane were added to the mixture and then, after a few minutes, the organic phase was separated by settling, washed with 25 cm3 of water and 25 cm3 of a saturated 10% sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 40-63 μm; diameter 5 cm; height 30 cm), elution was carried out with cyclohexane, and first a fraction of 500 cm3 was collected, followed by 50-cm3 fractions. Fractions 9 to 26 were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 5.9 g of 1-[(2-bromoethyl)thio]-3,5-difluorobenzene were obtained in the form of a colorless liquid. Infrared spectrum (CCl4): 3094, 1607, 1587, 1429, 1192, 1122, 988, 876, 841, and 667 cm−1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:41](=[N:42][CH:43]=2)[N:40]([C:44]([NH2:46])=[O:45])[CH2:39][CH2:38][CH2:37]3)O1.CCOC(C)=O>O>[CH3:12][N:11]([CH3:13])[C:9]([CH2:8][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[C:36]3[C:41](=[N:42][CH:43]=2)[N:40]([C:44]([NH2:46])=[O:45])[CH2:39][CH2:38][CH2:37]3)[CH:7]=[N:6][CH:5]=1)=[O:10]
Reactant: CN(C)C(=O)Cc1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3C(N)=O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Yield: 7.9 %

Procedure:
2-(5-Bromo-pyridin-3-yl)-N,N-dimethyl-acetamide (73 mg, 0.30 mmol) and 2.0 M Na2CO3 aqueous solution (0.30 mL, 0.60 mmol) are added into the crude 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide 1,4-dioxane solution (3.0 mL, 0.36 mmol) which is synthesized according to the procedure for Step 3 of Example 16. The Argon gas is bubbled through the solution for 5 min. Then PdCl2dppf (11 mg, 0.015 mmol) is added. The mixture is heated at 100° C. for 3.5 hrs before EtOAc (15 mL) and water (15 mL) are added. The aqueous layer is separated and extracted with EtOAc (2×10 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 8.0 mg of the titled product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[NH3:22]>C(O)C>[CH2:20]([O:19][C:17]([CH:11]([CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:15][CH2:14][CH2:13][C:12]([NH2:22])=[O:16])=[O:18])[CH3:21]
Reactant: CCOC(=O)C1(CCCOC2CCCCO2)CCCC1=O
Reactant: N
Solvent: CCO
Product: CCOC(=O)C(CCCOC1CCCCO1)CCCC(N)=O

Procedure:
A mixture of 0.5 g (1.67 mmol) 2-[3-(tetrahydropyranyloxy)propyl]-2-ethoxycarbonylcyclopentanone and 5 ml ethanol is saturated with ammonia gas at 5° in a thick-wall tube. The tube is sealed and heated to 80° for 17 h. The reaction mixture is cooled and then subjected to evaporation. The resulting oil is chromatographed using 4:1 ethylacetate/hexane +1% aqueous ammonia to yield 5-ethoxycarbonyl-5-[3-(tetrahydropyranyloxy)propyl]-valeramide; IR (neat): 3413, 3349, 1727, 1668 cm-1.
Reaction SMILES: [CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([N:5]([CH2:36][CH2:37][CH2:38][CH3:39])[C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[C:24]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[CH:11]=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)c1cccc(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)c1cccc(-c2ccc(C(=O)O)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of methyl 4-(6-(dibutylcarbamoyl)pyridin-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (158 mg, 0.30 mmol) in THF (2.0 mL) and MeOH (2.0 mL) was added 2N NaOH (1.5 mL, 3.00 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. At 0° C., the reaction mixture was neutralized to pH 4-5 with 1N HCl. The solution was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (146 mg, 95%). MS(ESI+) m/z 514.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6](O)=[O:7])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[F:54][C:55]([F:59])([F:58])[CH2:56][NH2:57]>CN(C=O)C>[F:54][C:55]([F:59])([F:58])[CH2:56][NH:57][C:6]([CH:4]1[CH2:5][C:2]([OH:1])([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:3]1)=[O:7]
Reactant: O=C(O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.3 %

Procedure:
To a stirred solution of 3-hydroxy-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 4, 0.050 g, 0.098 mmol) in DMF (0.5 mL) was added HOBt (0.013 g, 0.096 mmol), DIPEA (0.025 g, 0.193 mmol) EDCl.HCl (0.019 g, 0.099 mmol) and 2,2,2-Trifluoro-ethylamine hydrochloride (0.013 g, 0.096 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 18 h under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2×5 mL). Combined organic layer was washed with brine (5 mL), dried over sodium sulphate and evaporated in vacuo to get thick oil, 0.093 mg crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 2% methanol in DCM to afford thick yellow oil, which was re-purified by DCM in pentane (1:9) to afford white solid (0.020 g, 37.5%). 1H-NMR (400 MHz, CDCl3) δ: 2.55-2.57 (m, 2H), 2.87-2.91 (m, 3H), 3.67 (d, 1H, J=17.24), 3.96-4.01 (m, 2H), 4.08 (d, 1H, J=17.2 Hz), 4.71 (s, 1H), 5.97 (t, 1H, J=6.32 Hz), 7.55 (d, 2H, J=8.44 Hz), 7.64-7.6 (m, 4H). LC-MS (m/z): [M−H] 586.90.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[S:8]([NH2:11])(=[O:10])=[O:9].[BH4-].[Na+].Cl>C1COCC1.CO>[OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)C1COCCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)C1COCCC1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
4-Oxotetrahydropyran-3-sulfonamide (1.09 g) was dissolved in 2:1 THF/methanol (110 ml), sodium borohydride (0.23 g) was added in portions and the mixture was stirred at room temperature for 18 hours. Concentrated hydrochloric acid was then used to set the pH to 2 and then the solvent was removed under reduced pressure. The residue was purified by chromatography (solvent: dichloromethane/methanol). This gave the product (0.65 g) with a molecular weight of 181.2 g/mol (C5H11NO4S).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19].NCC#CC1C=CC([Cl:31])=CC=1C(=O)C1C=CC=CC=1>>[NH2:1][CH2:2][C:3]#[C:4][C:5]1([Cl:31])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19]
Reactant: NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: NCC#Cc1ccc(Cl)cc1C(=O)c1ccccc1
Product: NCC#CC1(Cl)C=CC=CC1C(=O)c1ccccc1Cl

Procedure:
The preparation of 3-amino-1-[4-chloro-2-(2-chlorobenzoyl)phenyl]propyne was conducted in the same manner as the preparation of 3-amino-1-[4-chloro-2-benzoylphenyl]propyne [Method A] to give pale yellow prisms, mp 81°-82° C.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1>CN(C)C=O>[CH3:32][C:27]1[CH:26]=[C:25]([NH:24][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:30]=[C:29]([CH3:31])[CH:28]=1
Reactant: O=C(O)c1cccnc1S
Reactant: Cc1cc(C)cc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylidine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:11][CH3:12])[C:9]#[N:10].CO>CCOCC.C(Cl)Cl>[C:13]1([C:8]([NH2:7])([CH2:11][CH3:12])[CH2:9][NH2:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(N)(C#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(N)(CN)c1ccccc1
Yield: 81 %

Procedure:
To a stirred suspension of lithium aluminum hydride (LAH, 7.0 g) in 250 mL of ether is added dropwise a solution of the compound of step 1(10.0 g) in 10 mL of ether at −70° C. The reaction mixture is stirred at −60° C. to −70° C. until TLC (10% MeOH in CH2Cl2) shows the disappearance of the starting material. The excess LAH is destroyed by cautious addition of a saturated aqueous Na2SO4 solution. The resulting mixture is filtered and solid is washed with EtOAc. The filtrate is dried over Na2SO4 and concentrated under vacuum to give 8.3 g of the title compound as clear oil.