Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]=[CH:13][C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH2:15]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1(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)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: C=CC1(B(O)O)C=CC=CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cccc(C=Cc2ccccc2)c1

Procedure:
Methyl 3-bromobenzoate (458 mg, 2 mmol), 1-styreneboronic acid pinacoyl ester (484 mg, 2.1 mmol), Na2CO3 (222 mg, 2.1 mmol), tetrakis(triphenylphosphino)palladium (116 mg, 0.1 mmol), water (4 mL) and 1,2-dimethoxyethane (6 mL) were stirred with reflux conditions for one hour, under nitrogen. The reaction mixture was diluted with water and was extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by trituration with Et2O. White crystals were obtained (393 mg, 82%). NMR 1H (ppm, CDCl3): 8.19 (t, J4=1.6 Hz, 1H), 7.91 (dt, J3=7.7 Hz, J4=1.3 Hz, 1H), 7.67 (d, J3=7.8 Hz, 1H), 7.52 (d, J3=7.3 Hz, 2H), 7.42 (t, J3=7.9 Hz, 1H), 7.36 (t, J3=7.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J3=16.3 Hz, 1H), 7.11 (d, J3=16.4 Hz, 1H), 3.06 (s, 3H).
Reaction SMILES: S.[Na].[Br:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]2[C:7]([C:8](=[O:27])[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([S:19](C)=O)[N:11]2[CH:16]2[CH2:18][CH2:17]2)=[CH:6][CH:5]=1>CN(C)C=O>[Br:3][C:4]1[C:13]([O:14][CH3:15])=[C:12]2[C:7]([C:8](=[O:27])[C:9]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([SH:19])[N:11]2[CH:16]2[CH2:17][CH2:18]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c(S(C)=O)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Agent: S
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Temperature: 50 °C

Procedure:
Anhydrous sodium hydrogen sulfide (Alfa Aesar, 53.3 mg, 0.95 mmol) is added in one portion to a solution of dimethylformamide (4.0 mL) containing 16 (158.1 mg, 0.37 mmol) at room temperature. The resulting solution is heated at 50° C. for 1 h and allowed to cool to room temperature. The reaction mixture is quenched by addition of a 5% aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (100 mL). The organic extract is washed with brine (50 mL) and evaporated to dryness under reduced pressure to give crude ethyl 7-bromo-1-cyclopropyl-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate. Rf 0 (ethyl acetate). LCMS m/z calcd for C16H1679BrNO4S ([M]+) 397. Found 398 ([M+H]+).
Reaction SMILES: COC1C=CC(C(F)(F)F)=CC=1N.C1N=C[N:16]([C:19](N2C=NC=C2)=[O:20])C=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29].O>C(Cl)Cl>[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:19]([NH2:16])=[O:20])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: COc1ccc(C(F)(F)F)cc1N
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(N)=O)cc2)ccn1
Reaction time: 16 h

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2Cl2 (15 mL) at 0° C. is added CDI (0.13 g). The resulting solution is allowed to warm to room temp. over 1 h, is stirred at room temp. for 16 h, then is treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g) from Step 2. The resulting yellow solution is stirred at room temp. for 72 h, then is treated with H2O (125 mL). The resulting aqueous mixture is extracted with EtOAc (2×150 mL). The combined organics are washed with a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue is triturated (90% EtOAc/10% hexane). The resulting white solids are collected by filtration and washed with EtOAc. The filtrate is concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-N)-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a light tan solid: TLC (100% EtOAc) Rf 0.62; 1H NMR (DMSO-d6) δ 2.76 (d, Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461 ((M+H)+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:65])[C@@H:7]([NH:13][C:14](=[O:64])[CH2:15][CH2:16][C@@H:17]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH:18][C:19](=[O:56])[CH2:20][CH2:21][C@@H:22]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:79]1[C:84](=[O:85])[CH2:83][CH2:82][C:80]1=[O:81])=[N+](C)C)C>>[O:81]=[C:80]1[CH2:82][CH2:83][C:84](=[O:85])[N:79]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][C@H:7]([NH:13][C:14](=[O:64])[CH2:15][CH2:16][C@@H:17]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[NH:18][C:19](=[O:56])[CH2:20][CH2:21][C@@H:22]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[NH:23][C:24](=[O:48])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:65]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
(S)-2-{(S)-4-tert-Butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}pentanedioic acid 1-tert-butyl ester (2.8 g, 3.02 mmol) was activated with TSTU (1.0 g, 3.325 mmol) using the same method as described above, giving crude (S)-2-{(S)-4-tert-butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}-pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester. LCMS (electrospray): m/z=1024 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.P(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7]
Reactant: O=C(O)CCCBr
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClP(Cl)Cl
Product: O=C(CCCBr)c1ccccc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Into 23.7 g of the benzene solution of 4-bromobutyric acid obtained in Example 5, was added 4.5 g of phosphorus trichloride (33 mmol) dropwise at 20° C. After the temperature was raised to 60 to 70° C., the mixture was stirred for three hours. Then, after the mixture was cooled to 20° C., the reaction solution was dropwise added into a suspension solution containing 20 g of benzene (256 mmol) and 13.3 g of aluminum chloride (100 mmol) at 10° C. After stirring the mixture at that temperature for 30 minutes, the temperature was raised to 20° C. and the mixture was further stirred for one hour and added into a 10% aqueous solution of hydrochloric acid that had been cooled to 10° C. Then, the aqueous phase was extracted with benzene, and the organic phase was washed with diluted hydrochloric acid and brine, followed by partially removing benzene by distillation under reduced pressure to give 92.1 g of a benzene solution of 4-bromobutyrophenone.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[CH3:13][N:14]1[CH:18](P(OCC)(=O)OCC)[C:17](=[O:27])[NH:16][C:15]1=[O:28]>>[CH3:13][N:14]1[C:18](=[CH:4][C:3]2[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])[C:17](=[O:27])[NH:16][C:15]1=[O:28]
Reactant: Cc1cccc([N+](=O)[O-])c1C=O
Reactant: CCOP(=O)(OCC)C1C(=O)NC(=O)N1C
Product: Cc1cccc([N+](=O)[O-])c1C=C1C(=O)NC(=O)N1C
Yield: 80 %

Procedure:
Reaction of 2-methyl-6-nitrobenzaldehyde with diethyl 1-methyl-2,4-dioxoimidazolidine-5-phosphonate according to procedure D provides the title compound as a mixture of geometrical isomers, m.p. 194°-197° C. in 80% yield.
Reaction SMILES: [CH2:1]([S:3][CH:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[C:8]([CH3:14])[C:7]=1[OH:15])[CH3:5])[CH3:2].CC(C)([O-])C.[K+].Cl[C:23]1[N:24]=[N:25][C:26]([Cl:31])=[CH:27][C:28]=1[O:29][CH3:30].O>O1CCOCC1.CS(C)=O>[Cl:31][C:26]1[N:25]=[N:24][C:23]([O:15][C:7]2[C:8]([CH3:14])=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[C:6]=2[CH:4]([S:3][CH2:1][CH3:2])[CH3:5])=[C:28]([O:29][CH3:30])[CH:27]=1
Reactant: COc1cc(Cl)nnc1Cl
Reactant: CCSC(C)c1c(C)cc(C)c(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCSC(C)c1c(C)cc(C)c(C)c1Oc1nnc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.9 %

Procedure:
In a mixed solvent of 1,4-dioxane (2 mL) and dimethylsulfoxide (2 mL) was dissolved 150 mg (0.670 mmol) of 2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenol obtained in Example 633(5), 93 mg (0.83 mmol) of potassium tert-butoxide was added to the solution in an ice bath, and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was again cooled in an ice bath, 120 mg (0.670 mmol) of 3,6-dichloro-4-methoxypyridazine was added to the mixture, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel chromatography (Wakogel C-100, hexane-ethyl acetate, gradient) and by preparative thin-layer chromatography (available from MERCK CO., 1.05744, 2 plates were used, developed by hexane:ethyl acetate=2:1) to obtain 26.7 mg (0.0728 mmol, Yield: 10.9%) of 6-chloro-3-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine. Also, 60.0 mg (0.163 mmol, Yield: 24.3%) of 3-chloro-6-{2-[1-(ethylsulfanyl)ethyl]-3,5,6-trimethylphenoxy}-4-methoxypyridazine was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:19](Br)=[C:18]([Cl:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[NH2:13][C:14]1[CH:21]=[CH:20][C:19]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH3:12])=[C:18]([Cl:23])[C:15]=1[C:16]#[N:17]
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: N#Cc1c(N)ccc(Br)c1Cl
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1ccc(N)c(C#N)c1Cl
Yield: 92.6 %

Procedure:
A stirred mixture of 5.7 grams (0.020 mole) of 5-chloro-2-methoxyphenylboronic acid, 3.3 grams (0.014 mole) of 2-amino-5-bromo-6-chlorobenzonitrile (prepared in Step A of this Example), 21 mL of aqueous 2M sodium carbonate, and 0.15 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 50 mL of toluene was heated at reflux for about 17 hours. After this time, 50 mL of ethyl acetate was added to the reaction mixture. The organic layer was separated and washed with 50 mL of water and then with 50 mL of an aqueous solution saturated with sodium chloride. The organic layer was then dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.8 grams of 2-amino-6-chloro-5-(5-chloro-2-methoxyphenyl)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)(C(OCC)=O)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C.O>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH:3]([CH2:1][CH3:2])[C:4]([OH:6])=[O:5])=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)C(CC)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 69.2 %

Procedure:
In 150 ml of ethanol was dissolved 37.18 g (0.12 mole) of diethyl 2-ethyl-2-(4-nitrophenyl)malonate and a solution of 30.41 g (0.76 mole) of sodium hydroxide in 100 ml of water was added and then heated under reflux for 3 hours on an oil bath. After the solvent was distilled off in vacuo, the residue was dissolved in 200 ml of water and then extracted with 300 ml of ether. The ether layer was removed and the water layer was acidified with conc. hydrochloric acid and extracted again with ether. The ether layer was separated, washed with saturated sodium chloride solution and dried over magnesium sulfate. The ether was distilled off in vacuo to give 17.25 g (0.083 mole, 69% yield) of 2-(4-nitrophenyl)-n-butyric acid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:7][C:6]=1[CH2:20][N:21](CC1C=CC(OC)=CC=1OC)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:26]([O:25][C:23]([C:22]1[N:21]=[CH:20][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=1[F:18])[CH:7]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2c(F)cccc2F)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2cc(Oc3c(F)cccc3F)ccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To an ice-water bath cooled solution of 4-(2,6-difluoro-phenoxy)-2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (1.09 g) in THF (10 mL) was added a solution of potassium tert-pentoxide (1.77 mL, 1.7 M in toluene); the mixture was stirred for 30 min at rt after addition; then the mixture was quenched with 2 M HCl (0.9 mL) diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (20 mL) and treated with thionyl chloride (0.15 mL) overnight. Then the reaction mixture was concentrated; the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (449 mg). LC MS ESI: 346 (M+1)+.
Reaction SMILES: [C:1]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])(=[O:3])[NH2:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>O1CCCC1>[CH3:14][N:15]([CH3:17])[CH:16]=[N:2][C:1]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CCOP(=O)(OCC)C(N)=O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(=O)N=CN(C)C

Procedure:
a solution of 54 parts of diethyl carbamoylphosphonate and 36 parts of dimethyl formamide dimethyl acetal was refluxed in 1000 parts of anhydrous tetrahydrofuran for eight hours. The solvent was removed under reduced pressure to give 70 parts of diethyl 1-dimethylaminomethyleneaminocarbonylphosphonate, nD24 = 1.4970.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([C:35]2[CH:40]=[CH:39][C:38]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:37][CH:36]=2)=[O:42])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1

Procedure:
4-{4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and N-(4-tert-butyl-phenyl)-6-chloro-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C27H30N4O3 [M+H]+: 459.2391. Found: 459.2390.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[CH2:36]([O:43][CH2:44][CH:45]([C:47]1[C:48]([Cl:54])=[N:49][C:50](Br)=[CH:51][CH:52]=1)[F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:36]([O:43][CH2:44][CH:45]([C:47]1[CH:52]=[CH:51][C:50]([C:18]2[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:10]3[O:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[C:12]([C:13]([NH:15][CH3:16])=[O:14])[C:11]=3[CH:17]=2)=[N:49][C:48]=1[Cl:54])[F:46])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: FC(COCc1ccccc1)c1ccc(Br)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C(F)COCc4ccccc4)c(Cl)n3)cc12
Temperature: 85 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (714 mg, 1.422 mmol) and 3-(2-(benzyloxy)-1-fluoroethyl)-6-bromo-2-chloropyridine (490 mg, 1.422 mmol) in 1,4-Dioxane (15 ml) and water (2 mL) was added K2CO3 (393 mg, 2.84 mmol) and Pd(dppf)Cl2 (100 mg, 0.137 mmol) under N2 protection. The resulting mixture was heated to 85° C. and stirred for 6 h. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-20% ethyl acetate/DCM) to provide 5-(5-(2-(benzyloxy)-1-fluoroethyl)-6-chloropyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (660 mg, yield: 67%). MS (M+H)+: 641.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].CN(P(N(C)C)(N(C)C)=O)C.C(N)CN>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:20]#[N:21])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1ccc(-c2nccc3c(Cl)cccc23)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: Cc1ccc(-c2nccc3c(C#N)cccc23)cc1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A mixture of 22 g of 1-(4-methylphenyl)-5-chloroisoquinoline, 74.4 g of copper cyanide and 420 ml of hexamethylphosphotriamide was heated overnight under reflux. After the reaction, the reaction mixture was poured into a mixture of ethylenediamine, water and benzene, and stirred for 30 minutes. The mixture was then filtered through Celite. The benzene layer as filtrate was washed in water, and dried, followed by distilling off the solvent. The residue was recrystallized from ether to afford 16.4 g of 1-(4-methylphenyl)-5-cyanoisoquinoline as colorless needles having a melting point of 131.8° to 132.4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:16][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:14][C:13]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:6][C:5]=1[O:55]C.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:13]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=3)=[CH:14][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:6][C:5]=1[OH:55]
Reactant: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methoxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (0.418 g, 0.53 mmol, 1 eq) in CH2Cl2 (9 mL) cooled to 0° C. was added BBr3 (IM in CH2Cl2) (0.800 mL, 0.53 mmol, 1 eq). The reaction was stirred at 0° C. for 40 min, poured over ice and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 to 30% EtOAc:hexane +1% Formic Acid) to afford 2-hydroxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (see next example) and the title compound (0.201 g, 50%) as a white foam. 1H NMR (DMSO-d6) δ 13.60 (bs, 1H); 11.10 (bs, 1H); 8.59 (bt, 1H); 7.96-7.92 (m, 6H); 7.78-7.66 (m, 4H); 7.48 (d, 1H); 7.26-7.10 (m, 5H); 6.26 (d, 1H); 6.21 (dd, 1H); 4.18 (dd, 2H); 3.24 (dd, 2H); 2.52 (t, 2H); 1.52 (m, 4H); 1.27 (m, 8H); IR (film) 3300, 2950, 2800, 1680, 1630, 1590, 1540, 1440, 1320, 1260, 1205, 1160, 1120, 1095, 1080, 990 cm−1; mass spectrum [(−)ESI], m/z 776 (M−H)−; Anal. Calcd. for C43H39F6NO5: C, 67.62; H, 5.15; N, 1.83, Found: C, 67.21; H, 5.11; N, 1.71.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>N1CCCCC1.C(O)C>[CH3:15][O:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:12][C:9]3[NH:8][C:7]([CH3:14])=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:10]=3[CH3:11])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCC(=O)O)c1C
Yield: 76.5 %

Procedure:
3-(2-carboxyethyl)-2,4-dimethyl-5-formylpyrrole (97.5 mg), 82 mg 6-methoxy-2-oxindole and 2 drops piperidine in 2 mL of ethanol were heated at 95° C. for overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 130 mg (76%) of the title compound as a yellow solid.