Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
A solution of 125 (443 mg, 0.80 mmol) and NH4Cl (37 mg, 0.68 mmol) in 2:1 mixture of EtOH/water (10.5 mL) was treated with iron powder (380 mg, 6.79 mmol) and stirred at reflux for 1 hour. The reaction mixture was then filtered through a celite pad and concentrated to afford title compound 126 that was used without further purification (440 mg, 100% yield). MS (m/z): 525.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)Cl)ccc1Cl
Temperature: 25 °C

Procedure:
4-chloro-3-methoxybenzoic acid, 3.7 g, was wet down with chloroform, 3 mL, and thionyl chloride, 6 mL, was added under an argon atmosphere. The resulting paste was subjected to reflux. After several minutes, the light yellow solution was cooled to room temperature and another 4.0 g of the substituted benzoic acid was added. The mixture was again brought to reflux for one hour. A still head was added to the flask in order to distill off chloroform and excess thionyl chloride at the minimum temperature possible. The still pot residue, containing the product, then solidified. Petroleum ether, 5 mL, was added to dissolve the solid with slight heating. Upon cooling to room temperature, the mother liquor was pipetted off gently, and the remaining solid was pumped in vacuo to obtain 7.3 grams of 4-chloro-3-methoxybenzoyl chloride as a light tan solid. Another 1.03 grams of less pure material could be obtained from the mother liquor.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[F:46])#[N:36]>>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:39][C:38]=1[F:46])#[N:36]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C#N)c(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-cyano-3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 2.93 Hz, 6H), 1.46 (dt, J=13.45, 6.72 Hz, 1H), 1.66 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 1.96 (ddd, J=13.27, 7.95, 7.64 Hz, 1H), 3.78 (t, J=7.83 Hz, 1H), 7.59-7.70 (m, 6H) 7.72-7.82 (m, 4H); Calcd for C26H21F4NO2 (M+H) 456.44, Found 456.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([CH3:29])([CH3:28])[CH2:24][NH:25]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:31]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([CH3:29])([CH3:28])[CH2:24][N:25]5[CH3:31])=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CNc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1CC(C)(C)c2ccc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound of Example 69 hydrogen chloride (20 mg) in DMF (5 mL) was added K2CO3 (50 mg), followed by MeI (50 μL). The mixture was stirred at room temperature for 2 h, and then treated with water, extracted with EtOAc (50 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica ghel to give a light yellow solid (10 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH2:20][C:21]([O:23]C)=O)=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C@@H:9]2[NH:8][C:21](=[O:23])[CH2:20][NH:19][C:17]2=[O:18])[CH2:16][CH2:15]1
Reactant: COC(=O)CNC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC(=O)[C@H](CC2CCOCC2)N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
A 250-mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-L-alanylglycinate (3.00 g, 8.71 mmol), 10 mL of CH2Cl2, and 5 mL of TFA. After 10 min at room temperature, the mixture was concentrated then dissolved in 2N NH3 in MeOH (20 mL) and stirred at room temperature for 4 h. The reaction was then concentrated and triturated with ether to give (3S)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N+:8]([O-:10])=[O:9])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-fluorophenol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-fluorophenoxy-1-nitrobenzene. The crude product may be used for further transformation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][C:35]#[N:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:36][CH2:35][CH2:34][C:33]#[N:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: N#CCCN
Product: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 55.4 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 48 (500 mg, 1.12 mmol) and 3-aminopropionitrile (0.41 mL, 5.6 mmol) were reacted to give the desired product 270 mg (55%). LC-MS: 436.0 (MH+, m/z), 2.17 (Rt, min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]=[C:10]=[O:11])[N:3]=1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21])=[CH2:13]>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:9][C:10]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[CH2:13])(=[O:21])=[O:22])=[O:11])[N:5]=1
Reactant: O=C=Nc1nc(Cl)nc(Cl)n1
Reactant: C=Cc1ccccc1S(N)(=O)=O
Solvent: CC#N
Product: C=Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)nc(Cl)n1
Reaction time: 16 h

Procedure:
A solution of 4,6-dichloro-1,3,5-triazin-2-yl isocyanate (0.87 g, 4.5 mmol) in acetonitrile (9 ml) is contacted with 2-ethenylbenzenesulfonamide (0.83 g, 4.5 mmol) and stirred for 16 hours. The mixture is then evaporated under reduced pressure to yield the title compound which is used directly in subsequent reactions.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH:6][CH2:7][CH3:8])[CH3:5].[C:11](Cl)(=[O:16])[CH2:12][C:13](Cl)=[O:14]>CCOCC>[CH2:7]([C:6]1[C:11]([OH:16])=[CH:12][C:13](=[O:14])[O:3][C:4]=1[CH3:5])[CH3:8]
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CCC=C(C)O[Si](C)(C)C
Solvent: CCOCC
Product: CCc1c(O)cc(=O)oc1C
Temperature: -78 °C
Yield: 42.3 %

Procedure:
In 200 mL of ether, was dissolved 13.6 g (85.9 mmol) of 2-trimethylsilyloxy-2-pentene, and 4.6 mL (47.3 mmol) of malonyl chloride was added dropwise to the solution while stirring the solution at −78° C. After the addition of malonyl chloride, the solution was stirred for 1 hour at −78° C., and then, stirred over night while gradually heating the solution to room temperature. The precipitate was filtered and washed with ether. As a result, 3.08 g (20.0 mmol, 42.3%) of 5-ethyl-4-hydroxy-6-methyl-2-pyrone was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH2:22][OH:23])=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C(Cl)Cl.CCN(CC)CC.[S:34](Cl)([CH3:37])(=[O:36])=[O:35]>O>[CH3:37][S:34]([O:23][CH2:22][C:17]1[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:20]([CH3:21])[O:19][N:18]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1onc(CO)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1onc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone (47.2 mg, 0.144 mmol), DCM, and Et3N (40.1 μl, 0.288 mmol). The solution was cooled to 0° C. before addition of Ms-Cl (13.47 μl, 0.173 mmol). The reaction was stirred at 0° C. for 30 min before addition of water. The layers were separated and the aqueous was extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate. To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate (58.4 mg, 0.144 mmol), DMF, and sodium azide (28.1 mg, 0.432 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting the aqueous with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone. To a round bottomed flask was added (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (50.8 mg, 0.144 mmol), toluene (3 mL), and trimethylphosphine solution (216 μl, 1M in toluene, 0.216 mmol). The reaction was stirred at room temperature over 2 days before purifying via Biotage (EtOAc/hex) to afford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepine. LC/MS m/z 309 [M+H]+; 1H NMR (400 MHz, Acetone) δ 7.70-7.76 (m, 1H), 7.63-7.70 (m, 1H), 7.32-7.49 (m, 6H), 5.10 (br. s, 1H), 4.10 (br. s, 1H), 2.68 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#[N:2].[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][N:11]=1>>[N:16]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:4]=1[CH2:3][C:1]#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: Nc1cccnc1N
Product: N#CCc1nc2cccnc2[nH]1
Temperature: 25 °C

Procedure:
Ethyl cyanoacetate (1.5 equivalents) and 2,3-diaminopyridine (1 equivalent) were heated at 185° C. for 30 minutes. The reaction mixture was cooled to room temperature and the black solid was triturated with ether. The desired product was thus obtained as a dark brown powder. LC/MS m/z 159.1 (MH+), Rt 0.44 minutes.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O-])([O-:12])=[O:11].[K+].[K+].C(=O)=O.Cl>O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1nc2ccccc2[nH]1
Temperature: 250 °C
Reaction time: 10 h
Yield: 72.8 %

Procedure:
A mixture of 118 g (1 mol) of benzimidazole, g (2 mol) of K2CO3 and 400 ml of liquid carbon dioxide was stirred in an autoclave at 250° C. under autogenous pressure for 10 hours. The solid output was pulverized, suspended in 2.5 L of water and brought to pH 3-4 with concentrated hydrochloric acid while being cooled with ice. The resulting precipitate was filtered off and recrystallized from water to give 118 g (73%) of benzimidazole-2-carboxylic acid (Compound No. 4); mp. 170° C. (dec.).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:54][S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([C:4]2[N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:6]=[C:2]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=3[S:55][CH3:54])[N:3]=2)[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[CH:45]=1)[CH3:48]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CSc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3SC)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 150 °C

Procedure:
A suspension of 66.3 (48 mg, 0.06 mmol), 2-(methylthio)phenylboronic acid (12.5 mg, 0.2 mmol), Na2CO3 (28 mg, 0.24 mmol) in 3:1 DME/H2O (2 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 150° C. for 5 min in microwave. The reaction mixture was then partionated between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated. The crude product of Intermediate 93.1 used as is for the next step. LCMS (4 min gradient) RT=4.87 min, 816.3 (M+H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH2:9][C:10]1[N:15]=[C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[N:13]=[C:12]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])[C:11]=1[N:30]=O.S(=O)(=O)(O)O>O.CN(C=O)C>[NH2:30][C:11]1[C:12]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])=[N:13][C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:15][C:10]=1[NH2:9]
Reactant: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N
Reaction time: 0.17 h
Yield: 12.4 %

Procedure:
Sodium dithionite (4 g) was added in portions to a suspension of the product from example 4, step (d) (8.4 g) in a mixture of water (35 ml) and DMF (15 ml) at 100° C. The resultant yellow solution was cooled in an ice bath and 50% aqueous sulphuric acid (15 ml) was added, giving a grey precipitate. The mixture was stirred for 10 min, then filtered, washing with water, ethanol and diethyl ether, to afford the subtitled product as a grey solid (1.0 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])C.[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](F)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:32]#[C:33][CH3:34]>C1COCC1>[CH3:13][O:15][C:16]([C:18]1([S:42]([C:39]2[CH:38]=[CH:37][C:36]([O:35][CH2:31][C:32]#[C:33][CH3:34])=[CH:41][CH:40]=2)(=[O:44])=[O:43])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17]
Reactant: CC#CCOc1ccc(S(=O)(=O)F)cc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
To a solution of diisopropylamine (1.58 mL, 11.3 mmol) in THF (25 mL) at 0° C. was added 2.5M n-BuLi (4.68 mL, 11.7 mmol) and the resulting mixture was stirred for 15 min at that temperature. The reaction mixture was cooled to −78° C. and a solution of 1-(tert-butyl)-4-methyl 1,4-piperidinecarboxylate (prepared from example 30, step 1) (2.67 g, 11.0 mmol) in THF (40 mL) was added. The resulting mixture was stirred for 1 hand a solution of 4-but-2-ynyloxy benzenesulfonyl fluoride (2.5 g, 11.0 mmol) in THF (25 mL) was added into it. After sting for 4 h at rt, the reaction was quenched with satd. aqueous NH4Cl solution and extracted with EtOAc, dried over anhydrous Na2SO4. The crude product was purified by silica gel chromatography to obtain 2.6 g (53%) of the product as a solid; 1H NMR (300 MHz, CDCl3) δ1.44 (s, 9H), 1.87 (m, 3H), 1.98 (m, 2H), 2.32 (m, 2H), 2.62 (m, 2H), 3.74 (s, 3H), 4.17 (m, 2), 4.74 (m, 2H), 7.09 (d, 2H, J=7.2 Hz), 7.71 (d, 2H, J=7.2 Hz).
Reaction SMILES: [ClH:1].O[C:3]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH2:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CC(=O)CC>[ClH:1].[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[CH2:20][CH2:21]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Agent: Cl
Solvent: CCC(C)=O
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Reaction time: 2 h

Procedure:
To 22.5 g (0.05 mole) of 4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride in 300 ml of butanone was added 200 ml of concentrated HCl. The mixture was refluxed with stirring for 2 hours then allowed to stir overnight at room temperature. The mixture was refluxed with stirring an additional 2 hours after which the solvent was removed. The remaining residue was recrystallized from butanone and butanone-diethyl ether to give the desired product, M.P. 160°-161.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:32])[C:21]#[C:22][CH2:23][O:24][Si](C(C)(C)C)(C)C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:32])[C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:33]#[N:34])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2ccc(NC(=O)C#CCO)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
N-[4-[(3-Bromophenyl)amino]-3-cyano-6-quinolinyl]-4-(tert-butyl-dimethyl-silanyloxy)-2-butynamide (0.120 g, 0.224 mmol) was dissolved in a 25 ml solution (acetic acid:tetrahydrofuran:water=3:1:1) and stirred overnight at 25° C. The reaction was poured into ethyl acetate and washed with saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.085 g of yellow solid (90%); ESMS m/z 421.2 (M+H+); mp 253-254° C.(dec).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[CH:21][C:11]=2[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[CH3:27][NH2:28].[BH4-].[Na+].O>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:24]=[C:23]([CH2:25][NH:28][CH3:27])[CH:22]=[CH:21][C:11]=2[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1cc(F)cc(C#N)c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1ccc(OCC(=O)OC(C)(C)C)c(-c2cc(F)cc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-formylphenoxy)acetate (21) (120 g, 338 mmol) and MeNH2 (203 mL of a 2M solution in THF, 405 mmol) in methanol (300 mL) was stirred at room temperature for 2 h. Sodium borohydride (12 g, 316 mmol) was added, and the resulting mixture was stirred at room temperature for additional 2 h. Water (30 mL) was added and the MeOH was removed in vacuo. The resulting solution was extracted with EA (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-((methylamino)methyl)phenoxy)acetate (22) was used in the next reaction without further purification.
Reaction SMILES: B(O)O.C([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)(=[O:11])=[O:10])(C)(C)C.Br[C:20]1[N:21]=[C:22]([O:25][CH3:26])[S:23][CH:24]=1>>[CH3:26][O:25][C:22]1[SH:23]=[CH:24][CH:20]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH2:8])(=[O:10])=[O:11])=[CH:13][C:14]=2[CH3:18])[N:21]=1
Reactant: Cc1cccc(S(=O)(=O)NC(C)(C)C)c1
Reactant: COc1nc(Br)cs1
Agent: OBO
Product: COC1=NC(c2ccc(S(N)(=O)=O)cc2C)C=[SH]1
Yield: 24.6 %

Procedure:
This compound was prepared analogously to Example 52, starting from N-tert-butyl-3-methyl-benzenesulfonamide boronic acid (1.0 g, 3.69 mmol) and 4-bromo-2-methoxy-thiazole (0.78 g, 4.05 mmol, 1.1 equiv.) After purification on silica-gel with n-heptane/tert.butylmethyl ether 510 mg of the t-butyl protected sulfonamide were obtained. Deprotection analogous to Example 98 yielded 260 mg of the title compound as a light yellow solid. MS (ES): m/e 270 (M−H)
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)=[CH:8][CH:7]=1.[OH-].[Li+]>>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[N:15]1[CH2:16][CH2:17][CH:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:3]([OH:42])=[O:2])=[CH:7][CH:8]=2)[CH2:14]1
Reactant: COC(=O)C(Cc1ccc(OC2CCN(c3nc4ccccc4o3)C2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(c1ccccc1)c1ccccc1NC(Cc1ccc(OC2CCN(c3nc4ccccc4o3)C2)cc1)C(=O)O
Yield: 58.3 %

Procedure:
The title compound (115 mg) was prepared from 200 mg (0.36 mmol) of 3-[4-(1-Benzoxazol-2-yl-pyrrolidin-3-yloxy)-phenyl]-2-(2-benzoyl-phenylamino)-propionic acid methyl ester and 18 mg (0.43 mmol, 1.2 equiv.) of lithium hydroxide according to the method of Example 32 followed by purification via silica gel flash column chromatography using DCM/MeOH 90/10 as eluent: low resolution MS (ES) m/e 546.0 (MH−); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 30-80% CH3CN in H2O with 0.1% TFA buffer; 25 minutes; 1 mL/min); tr=17.92 min (t0=3 min). Daicel Chiral OD-H (4.6×250 mm, 5 m; 0.7 mL/min; inj volume 3 mL, UV 230 nM; 40/60/0.1 IPA/Hexane/TEA; 30 min); tr=6.8 min and 10.0 min.