Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:28])([C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])C(O)=O.[Br:29]Br.FF>C(O)CO.O>[F:1][C:2]([Br:29])([F:28])[C:6]([F:27])([F:26])[C:7]([F:25])([F:24])[C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: BrBr
Agent: FF
Solvent: O
Solvent: OCCO
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Temperature: 30 °C
Yield: 93.2 %

Procedure:
Perfluorononanoic acid 100 g (0.215 mole), bromine 41 g (0.258 mole) and Freon 113 (500 ml) were mixed in a 2-liter Teflon plastic bottle. This plastic reactor was equipped with a Teflon-coated magnetic stir bar, inlet and outlet tubes made of Teflon-FEP, and a thermocouple coated with Teflon-FEP. The outlet tube was connected to a condensor which was chilled with an ethylene glycol-water mixture. The acid solution was warmed to 30 ° C. through agitation while the reactor was purged of air by flushing it with an inert gas, such as nitrogen, through the inlet tube; The nitrogen flow was terminated and fluorine gas was bubbled into the mixture at 30 cc/min. The fluorine, supplied by Air Products, was used without further purification. The fluorine flow rate was controlled with a Monel needle valve and monitored with a Hastings mass flow transducer. Despite an exothermic reaction occurring immediately, the reaction temperature was kept at 30°-40° C. throughout the reactor by external cooling. The fluorine flow was maintained until the color of the solution turned from deep red to light yellow. Approximately 2.2 fold excess of fluorine (based on the initial amount of acid used) was required to produce this result. After the fluorine gas was terminated, the reactor was again purged with nitrogen and the mixture was carefully poured into water. The organic precipitate was washed with water containing a small amount of sodium thiosulfite, and then dried over magnesium sulfate. Fractional distillation of the precipitate produced 100 grams of perfluorooctyl bromide (97% yield) having a boiling point between 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>ClCCl>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH3:10])[C:5]([CH2:9][OH:16])=[N:6][CH:7]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1c(Br)c[n+]([O-])c(C)c1C
Solvent: ClCCl
Product: COc1c(Br)cnc(CO)c1C
Reaction time: 8 h

Procedure:
5-Bromo-4-methoxy-2,3-dimethylpyridine 1-oxide (4.91 g) was dissolved in dichloromethane (60 ml), and trifluoroacetic anhydride (20 ml) was then added to the solution at room temperature. The resulting mixture was stirred overnight. Thereafter, the reaction solution was concentrated, and the concentrated solution was then dissolved in methanol (50 ml). The resulting mixture was stirred at 50° C. for 1 hour. The reaction solution was concentrated. The residue was dissolved in dichloromethane, and was then washed with a saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the filtrate was then concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain the title compound (3.43 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12].[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([S:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:24]1[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:27]=[CH:26][CH:25]=1)(=[O:13])=[O:12])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Temperature: 97 °C
Yield: 91.6 %

Procedure:
To 100B (3.48 g, 11.8 mmol), 3A (3.0 g, 14.2 mmol) and sodium carbonate (23.7 mL, 2M, 47.4 mmol) in 1,2 dimethoxyethane (100 mL, flushed and degassed (3×) with nitrogen) was added Pd(PPh3)4 (2.74 g, 2.37 mmol). The reaction was heated to 97° C. for 3 h. The catalyst was filtered over celite and washed with ethyl acetate. The organic layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 4.11 g of product 10° C. (91% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.09 (t, J=7.46 Hz, 3H) 1.25 (s, 9H) 2.87-3.04 (m, 2H) 6.24-6.44 (m, 2H) 7.46 (dd, J=3.30, 1.83 Hz, 1H) 8.24 (d, J=2.20 Hz, 1H) 8.31 (d, J=8.56 Hz, 1H) 8.45 (dd, J=8.80, 2.45 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:32]=3[O:31][CH2:29][CH3:30])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1c(C=O)cccc1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOc1c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cccc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-ethoxy-3-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 543.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[NH:18]C(=O)C)[CH:7]=[CH:8][C:9]=1[Cl:10]>COCCO>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[C:12]([NH2:18])=[CH:13][CH:14]=[C:15]([F:17])[CH:16]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(=O)Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.08 mol of an approximately 45% aqueous potassium hydroxide solution is added to a suspension of 6.3 g (0.02 mol, purity: 95%) N-(3′,4′-dichloro-5-fluorobiphenyl-2-yl)acetamide and 12 ml 2-methoxyethanol. This is heated to 100° C., stirred for 4 hours, cooled and the solvent is distilled off in a vacuum. The residue is mixed with ice water and extracted several times with toluene.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:28].[Na+]>C(#N)C>[I:28][CH2:2][O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: [I-]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCI

Procedure:
2,2-Dimethyl-3-(N-CBz-D-valyloxy)-propionic acid chloromethyl ester (2.4 g, 6 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.26 g, 8.4 mmole) was added to the solution. After reaction at 70° C. for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. 2.68 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=O)[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[S:22])[CH2:12][C:11]3([CH3:20])[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC1(C)CC(=O)Nc2ccc(-c3cccc(F)c3)cc21
Solvent: c1ccncc1
Product: CC1(C)CC(=S)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
Prepared by heating under reflux overnight a mixture of 6-(3-fluorophenyl)-4,4-dimethyl-3,4-dihydroquinoline-2(1H)-one and an equal weight of phosphorus pentasulfide was stirred in pyridine. Workup as in the previous example gave a yellow solid, mp 209-211° C. 1H-NMR (DMSO-d6) δ 12.34 (s, 1H), 7.65 (d, 1H J=2.2 Hz) 7.57 (dd, 1H J1=8.24 J2=2.2 Hz), 7.51 (m, 3H), 7.18 (m, 2H), 2.84 (s, 2H), 1.26 (s, 6H). MS m/z 284 [M−H]− Anal. Calc. For C17H16FlNS: C, 71.55, H, 5.65, N, 4.91. Found: C, 71.18, H, 5.59, N, 4.82.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=1)=[O:7]
Reactant: CC(C)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL round bottom flask, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield the title compound as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: [Br:1][C:2]1[C:8](=[O:9])[C:7](OC)=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:12]>CO>[NH2:12][C:7]1[C:8](=[O:9])[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccccc(Br)c1=O
Reactant: N
Solvent: CO
Product: Nc1ccccc(Br)c1=O
Temperature: 80 °C

Procedure:
A solution of 7-bromo-2-methoxy-2,4,6-cycloheptatrien-1-one [1.0 g, described by T. Nozol et al., Proc. Japan Acad., 27, 556-60 (1951), (CA 46, 7560c)] in methanol (30 ml) is cooled to -20° C and saturated with gaseous ammonia. The reaction mixture is heated in a pressure bottle at 80° C for 4 hours and cooled to -70° C. The bottle is opened and the solvent is removed under reduced pressure. The residue is boiled with ethyl acetate and the ethyl acetate extract is evaporated to give 2-amino-7-bromo-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[CH2:10][C:3]=23)[CH2:27][CH2:26]1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccnc3c2CC2(CN4CCC2CC4)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of 97 mg (0.387 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 1 mL of 1-methylpiperazine was heated to reflux under a nitrogen atmosphere and stirred for 18 hours. Upon cooling to ambient temperature, the diluted with 40 mL of water, basicified with 2 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel using a 4:1 mixture of ammoniated chloroform/methanol to provide 59 mg (48%) of the title compound as an amber oil: electrospray MS (m/z, relative intensity) 315 ([MH]+).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[O:28])=[CH:23][CH:22]=1.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)=[O:28])=[CH:30][CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Yield: 29.2 %

Procedure:
Benzoyl peroxide (1 g) was added to a solution of 4-methoxyphenyl-4-methylphenyl methanone (22.6 g) and N-bromosuccinimide (17.8 g) in CCl4 (100 ml). The mixture was heated under reflux for 3.25 h, then cooled to 0°. The precipitated succinimide was filtered off, the filtrate evaporated and the residue purified by crystallisation from cyclohexane to give the title compound (8.9 g), m.p. 76°-78°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CSC(CCCCN=[N+]=[N-])CCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CSC(CCCCN)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
To a solution of 0.1 g (0.28 mmol) ethyl 8-azido-4-[3-(3-pyridyl)propyl]-3-thia-octanoate in 0.7 ml tetrahydrofuran is added 0.082 g triphenylphosphine followed by 0.01 ml water. The mixture is stirred at room temperature for 52 h and then evaporated to give ethyl 8-amino-4-[3-(3-pyridyl)propyl]-3-thia-octanoate, NMR (CDCl3): delta 4.2 (q,2H), 3.2 (s,2H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1.C[O:28][B:29](OC)[O:30]C>>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:3]=[C:2]([B:29]([OH:30])[OH:28])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Reactant: COB(OC)OC
Product: Cc1nc2c(B(O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(2,3-dichlorobenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.9 g, 1.977 mmol) using Method A with trimethylborate to give the product (82 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 2.97-3.12 (m, 4H) 3.69-3.77 (m, 4H) 5.57 (s, 2H) 6.32 (dd, J=7.83, 1.01 Hz, 1H) 7.12 (d, J=2.02 Hz, 1H) 7.26 (t, J=7.96 Hz, 1H) 7.36 (d, J=2.02 Hz, 1H) 7.61 (dd, J=8.08, 1.26 Hz, 1H) 8.66 (s, 2H); MS (ES+) m/z 420.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:22])[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14](C(OCC)=O)[CH2:13][CH2:12]1.[Br:23]C1C=CC(CC(O)=O)=CC=1>>[Br:23][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:1])=[O:22])=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCC(CC(=O)c2ccc(O)cc2O)CC1
Product: O=C(Cc1ccc(Br)cc1)c1ccc(O)cc1O
Yield: 27.9 %

Procedure:
Followed Step 4 of Intermediate C, starting with 2-(4-bromophenyl)acetic acid to give product as an orange powder (20 g, 27.9%). MS (ESI): m/z 307.0, 309.0 [M+1]+, [M+3]+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH3:30])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:28][CH2:29][CH3:30])[C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1

Procedure:
A mixture of methyl 2-[(4-{3-[(2,4-difluorobenzyl)(propyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (0.184 g, 0.382 mmol) and lithium hydroxide (0.018 g, 0.76 mmol) in THF (2 ml) and water (2 ml) was heated at 150 degrees for 7 minutes. The mixture was diluted with water, acidified with hydrochloric acid and extracted with methylene chloride. The combined extracts were dried with magnesium sulfate and evaporated to give 2-[(4-{3-[(2,4-difluorobenzyl)(propyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid.
Reaction SMILES: [CH3:1][N:2]1C(=O)CCC1.Cl[C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(C)(C)C)=[C:11]([C:22]#[C:23][CH3:24])[C:10]=1[C:25]([F:28])([F:27])[F:26].C([Cu])#N.[OH-].[NH4+]>CCOCC>[CH3:24][C:23]1[NH:15][C:12]2[C:11]([CH:22]=1)=[C:10]([C:25]([F:26])([F:27])[F:28])[C:9]([C:1]#[N:2])=[CH:14][CH:13]=2
Reactant: CC#Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Temperature: 195 °C
Yield: 64 %

Procedure:
An NMP solution (150 mL) of N-[4-chloro-2-(1-propyn-1-yl)-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (10 g, 31.5 mmol) was treated with CuCN (11.3 g, 126 mmol) and the resulting mixture was heated at 195° C. for 90 h. Two reactions were carried out simultaneously. The combined dark brown reaction mixture was poured into crushed ice (250 mL) containing conc. ammonium hydroxide (100 mL). The resulting slurry was stirred with the addition of Et2O and filtered through celite. The filtrate was diluted with Et2O and partitioned. The aqueous portion was extracted with Et2O four times. The combined organic portions were washed with brine and dried (MgSO4). Filtration and concentration in vacuo followed by radial chromatography (SiO2, 0-60% EtOAc-hexanes gradient) afforded the title compound as a solid (9 g, 64%):
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:36]>CN(C)C=O>[CH3:36][N:21]([CH2:20][CH2:19][C:18]1[CH:29]=[CH:30][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:31])[F:32])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 101.2 %

Procedure:
To tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) (0.021 g, 0.047 mmol) in anhydrous dimethylformamide (0.023 mL) at 0° C. was added sodium hydride (60% oil dispersion, 0.012 g, 0.30 mmol) and stirred in ice bath for 5 minutes. Iodomethane (0.013 g, 0.094 mmol) was added and the yellow solution immediately turned white. After 10 minutes, the reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated providing the title compound as a yellow oil (0.022 g, 97%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.12 (d, J=8.2 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.39 (dt, J=8.0, 1.0 Hz, 2H), 7.37-7.20 (m, 2H), 3.47 (s, 2H), 2.86 (s, 2H), 1.57 (s, 3H), 1.44 (d, J=13.7 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 463 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH:62]1([NH:65][CH2:66][C@H:67]2[CH2:71][CH2:70][CH2:69][NH:68]2)[CH2:64][CH2:63]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:62]1([NH:65][CH2:66][C@H:67]2[CH2:71][CH2:70][CH2:69][N:68]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:64][CH2:63]1
Reactant: C1CN[C@@H](CNC2CC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a mixture of 5-[5-(2,6-dichlorophenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), EDAC (76 mg, 2 eq.), HOBt (27 mg, 1 eq.) in DMF (4 mL) was added triethyamine (0.08 mL, 0.57 mmol) and cyclopropyl-(R)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL). After stirring at rt for 18 h, the reaction was basified with sodium bicarbonate, followed by extraction with 5% of methanol in dichloromethane. After concentration, the residue was purified on a silica gel column eluting with 5% of methanol in dichloromethane to give 80 mg (64%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH2:14]([O:21][NH:22][C:23]([C@H:25]1[C@@H:30]([CH3:31])[N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:28][CH2:27][NH:26]1)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1.N1C=CC=CC=1>[CH2:14]([O:21][NH:22][C:23]([C@H:25]1[C@@H:30]([CH3:31])[N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH2:27][N:26]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1[C@H](C(=O)NOCc2ccccc2)NCCN1S(C)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@H](C)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
A solution of 4-methoxybenzenesulfonyl chloride (284 mg) in dioxane (2 ml) was added to a solution of (2R,3R)-N-benzyloxy-4-methanesulfonyl-3-methyl-2-piperazinecarboxamide hydrochloride (200 mg) in pyridine (2 ml) with cooling on an ice bath. The mixture was stirred at ambient temperature for 3.5 hours. 4-Methoxybenzene-sulfonyl chloride (60 mg) in dioxane (1 ml) was added thereto, and the mixture was stirred at ambient temperature for 2 hours. 4-Methoxybenzenesulfonyl chloride (60 mg) in dioxane (1 ml) was added to the mixture. The reaction mixture was stirred at ambient temperature for 2 hours, and the reaction was quenched by adding 3-(N,N-dimethyl-amino)propylamine (0.1 ml). The mixture was partitioned between 0.6N HCl and AcOEt. The organic layer was washed with 0.6N HCl, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt in n-hexane 60% to 80%) to give 273 mg of (2R,3R)-N-benzyloxy-4-methanesulfonyl-1-(4-methoxy-benzenesulfonyl)-3-methyl-2-piperazinecarboxamide as an amorphous powder.