Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]I.[OH-].[Na+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH3:27])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1nc(COCc2ccccc2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 22 %

Procedure:
In 50 ml of dry tetrahydrofuran was dissolved 15 g (44 mmol) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (16a). To this solution was added 6.87 g (48.4 mmol) of methyl iodide under ice-cooling, further followed by addition of 1.94 g (48.4 mmol) of sodium hydroxide and 100 mg of tetrabutylammonium bromide. After the ice-water bath was removed, the mixture was stirred for 1 hour. This reaction mixture was concentrated under reduced pressure and the residue was neutralized with hydrochloric acid and sodium hydrogen carbonate to be weakly basic and extracted twice with ethyl acetate. The pooled organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was fractionated by silica gel chromatography (3% ethyl acetate in methylene chloride). From the first fraction, 3.5 g (yield 22%) of the objective position isomer (17a') was obtained as oil. From the subsequent fraction, 10.4 g (yield 67%) of the objective 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazole (17a) was obtained as oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[NH:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:61]([O:63][CH3:64])=[O:62])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCN(CC)CC>[NH:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:12]([C:20]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:61]([O:63][CH3:64])=[O:62])[CH2:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 18 h

Procedure:
9.5 ml NEt3, 13 g HOBT and 17 g BOC-Phe-OH are added to 35 g H-(D)Trp-Lys(Z)-OMe hydrochloride in 350 ml DMF. The solution is cooled to -20° C. and 14.5 g DCCI dissolved in 50 ml DMF are added. The reaction mixture is stirred for ca. 18 hrs. at 0° C. and then for 1 day at room temperature. The precipitated dicyclohexyl-urea is filtered off and the filtrate is concentrated, diluted with methanol and H2O added until precipitation occurs. After filtration the residue is washed with MeOH/H2O (4:1) and dried to yield the title compound:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1COCC1.C(OCC)(=O)C>[Cl:14][CH2:15][C:16]([N:11]1[CH2:10][CH2:9][S:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCS2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCl)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (620 mg, 3.16 mmol) in THF (10 mL) was added 2-chloroacetyl chloride (0.277 mL, 3.48 mmol). The resulting mixture was then stirred at 60° C. for 10 minutes The mixture was then diluted with ethyl acetate and washed with water (3×), 1:1 water:saturated sodium carbonate, and brine. The organic phase was dried, filtered, and concentrated, giving the desired product (860 mg, 100%). 1H NMR (DMSO-d6) δ 8.36 (d, J=2.1 Hz, 1H), 7.96 (dd, J=8.7, 2.1 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 4.63 (s, 2H), 3.99-3.92 (m, 2H), 3.39-3.33 (m, 2H); ESI-MS (m/z, %): 295 (M+Na, 68), 273 (MH+, 100), 197 (43).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=O.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([C:5]2[NH:17][CH2:16][CH2:15][N:18]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: NCCN
Product: Cc1cccc(C2=NCCN2)c1[N+](=O)[O-]
Temperature: 190 °C

Procedure:
A solution of methyl 3-methyl-2-nitrobenzoate 3.13 g (16.1 mmol) in ethylenediamine (15 mL) was heated at reflux for 1.5 hours, at which point the solvent was removed at 130° C. under reduced pressure. The residue was then heated at 190° C. for 1.25 hours before being cooled on ice and purified by flash column chromatography (silica gel, 1% to 10% methanol in dichloromethane) to give the title compound of Step A (0.35 g) as a brown oil.
Reaction SMILES: C(C1C=CC(OCC2ON=C(CC3C=C(C=CC=3)[C:19]([OH:21])=[O:20])N=2)=C(C)C=1O)(=O)C.[OH:29][C:30]1[C:35]([CH3:36])=[C:34]([O:37][CH2:38][C:39]2[O:43][N:42]=[C:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=3)[N:40]=2)[CH:33]=[CH:32][C:31]=1[C:52](=[O:54])[CH3:53]>>[C:52]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[O:43][N:42]=[C:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([C:19]([OH:21])=[O:20])=[CH:47][CH:46]=3)[N:40]=2)=[C:35]([CH3:36])[C:30]=1[OH:29])(=[O:54])[CH3:53]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(C(=O)O)cc3)no2)c(C)c1O

Procedure:
The title compound is prepared essentially as described for 3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid, employing 1-{2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone. 1H NMR (DMSO-d6) δ 12.84 (s, 1H), 12.80 (s, 1H), 7.86 (m. 2H), 7.78 (d, 1H), 7.38 (d, 2H), 6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s, 3H), 1.99 (s, 3H). LC-MS (m/e): 381 (M−1).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][C:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])([F:23])[F:22].CCOC(C)=O>C(Cl)Cl>[N:9]1[CH:10]=[CH:11][N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:21]([F:20])([F:22])[F:23])=[O:27])[CH2:3][CH2:2]2)[N:8]=1
Reactant: c1cnc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2nccnn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Compound 3 is prepared according to synthesis method 2: 0.4 g (2.42 mmoles) of derivative 5a is placed in 10 ml of CH2Cl2. 0.5 ml (3.63 mmoles) of triethylamine is added. At 0° C., 0.4 ml (2.66 mmoles) of trifluoromethylbenzoyl chloride is added drop by drop, the reaction medium is stirred at ambient temperature for 18 hours. After concentrating the reaction medium to dryness, the residue obtained is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phase is concentrated. The residue obtained is purified by silica flash chromatography (CH2Cl2,100%). 0.72 g of yellow powder is isolated (yield: 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[NH2:32][C@@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20](=[O:31])[C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25][CH:26]=3)[C:16]([NH:32][C@@H:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[O:18])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(C(=O)N[C@@H](Cc2ccc(-c3ncc(Br)cn3)cc2)C(=O)O)cc1
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(-c2ncc(Br)cn2)cc1)NC(=O)c1ccc(C(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirring solution of (S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propanoic acid INT-27 (1.50 g, 3.10 mmol) in DMF (15 mL) were added tert-butyl D-alaninate (680.0 mg, 3.73 mmol) and Et3N (802.3 mg, 6.2 mmol). The reaction was stirred for 1 hour at 0° C. and then HATU (877.5 mg, 3.37 mmol) in 2 mL DMF was added. The reaction was stirred for 1 hour at 0° C. and then warmed to room temperature with stirring for 18 hours. The reaction solution was extracted with aqueous NaHCO3 (3×20 mL). The combined organics were dried over MgSO4 and evaporated. The crude product was purified by column chromatography (50%) EA in hexanes) to afford 1.44 g (76%) of tert-butyl ((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-propanoyl)-D-alaninate INT-32 as a solid powder. LCMS-ESI (m/z) calculated for C31H37BrN4O4: 609.6. found 610.2 [M+H]+, tR=4.05 min. (Method 16). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 2H), 8.49 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2 Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 7.73 (t, J=7.4 Hz, 2H), 7.54-7.37 (m, 4H), 4.85 (td, J=10.1, 4.6 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H), 3.24-2.97 (m, 2H), 1.50-1.29 (m, 9H), 1.32-1.17 (m, 12H).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@H:13]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].[NH:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:29]([C:31](O)=[O:32])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CCN(CC)CC>[NH:28]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:29]([C:31]([NH:12][C@H:13]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:32])[CH3:30]
Reactant: CC[C@H](C)[C@H](N)C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
23.61 g of tosylate of H-Ile-OBzl and 11.35 g of Boc-Ala-OH are suspended in 500 ml of AcOEt. To this mixture 6.07 g of Et3N and 8.92 g of HOBt and then 12.65 g of WSC are added with cooling in an ice bath. Stirring is continued whilst cooling the reaction mixture in an ice bath (2 hrs) then at ambient temperature for 15 hrs. To this mixture a 5% aqueous solution of citric acid is added. The organic phase is washed with a 5% aqueous solution of sodium bicarbonate, with a saturated aqueous solution of sodium chloride. The organic phase is dried over Na2SO4 and evaporated to dryness. The oily product is obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])O[C:8](=[O:9])[CH:3]1[CH2:4][CH:5]=[CH:6][CH3:7].C1(CN)C=CC=C(C[NH2:20])C=1>C1(C)C(C)=CC=CC=1>[CH3:1][CH:2]1[C:11](=[O:12])[NH:20][C:8](=[O:9])[CH:3]1[CH2:4][CH:5]=[CH:6][CH3:7]
Reactant: CC=CCC1C(=O)OC(=O)C1C
Reactant: NCc1cccc(CN)c1
Solvent: Cc1ccccc1C
Product: CC=CCC1C(=O)NC(=O)C1C
Temperature: 200 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a 1000 ml flask replaced with nitrogen 257.4 g (1.26 mol) of allyl-bicyclo 2.2.1!hept-5-ene-2,3-dicarboxylic acid anhydride and 300 ml of xylene were charged. To the mixture was added 81.4 g (0.60 mol) of m-xylylenediamine over 1.5 hours with heating and stirring while refluxing xylene. The reaction was continued for 3 hours while separating and removing water produced by the reaction by a water separator, and then the solvent, xylene, was removed by distillation. Thereafter, the content of the flask was treated with heat at 200° C. under reduced pressure of 1 Torr for 1 hour while stirring, thus obtaining 301.8 g (yield: 99%) of the target N,N'-m-xylylene-bis(allyl-bicyclo 2.2.1!hept-5-ene-2,3-dicarboximide), of which the chemical structure is shown by the following formula 6!. This compound is hereinafter abbreviated to BANI-mX. ##STR10##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]=[C:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.[OH-].[K+:14].C(O)COCCOCCO>CO>[O:1]1[CH2:2][CH2:3][N:4]([CH:7]=[C:8]([CH3:12])[C:9]([O-:11])=[O:10])[CH2:5][CH2:6]1.[K+:14]
Reactant: CC(=CN1CCOCC1)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: CO
Product: CC(=CN1CCOCC1)C(=O)[O-]

Procedure:
To a small beaker was added 34.2 g (0.20 mole) of crude morpholinomethacrylic acid (Example II compound) and 60 ml methanol. The mixture was stirred until a clear solution resulted. Then, a solution of 12.3 g (0.20 mole) 91% potassium hydroxide in 50 ml methanol was added. The resulting solution was only slightly basic (pH = 8-9). Triethyleneglycol, 40 g, was added and the resulting solution was stripped on a rotary evaporator to remove methanol and water. A slightly viscous solution, that was 51% by weight of the title salt, was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[CH3:9])=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.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>[F:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([CH:18]=2)[C:15]([O:14][CH3:13])=[O:16])=[CH:3][CH:4]=1)([F:11])[CH3:9]
Reactant: CC(F)(F)c1ccc(Br)cc1
Reactant: COC(=O)c1cncc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cncc(-c2ccc(C(C)(F)F)cc2)c1
Reaction time: 0.17 h

Procedure:
A solution of 2.98 g (13.3 mmol) of the compound from Example 48A in toluene (25.0 ml) was admixed under argon at RT with 3.62 g (16.7 mmol) of the compound from Example 33A in ethanol (8.4 ml) and 2.03 g (14.7 mmol) of potassium carbonate. After stirring for 10 min, 1.54 g (1.34 mmol) of tetrakis(triphenylphosphine)palladium and then 2.33 g (40.0 mmol) of potassium fluoride in water (5.8 ml) were added. The mixture was stirred under reflux for 8 h, and the reaction solution was cooled and diluted with ethyl acetate. The reaction solution was washed in water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by means of column chromatography (silica gel, dichloromethane/methanol 100:1→80:1). Yield: 2.62 g (69% of theory, 4:1 mixture of methyl and ethyl ester)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[CH3:27][C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.C(OCC)(=O)C>[Cl:26][C:4]1[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:7]=[C:2]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=2[CH3:27])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2cc(-c3c[nH]c4ncccc34)cc(Cl)n2)c1C
Yield: 13.5 %

Procedure:
To a solution of Example 7a (0.08 g, 0.2 mmol), in 2 mL dimethoxyethane/ethanol/water (7:2:3) was added 2,3-dimethylphenylboronic acid (0.036 g, 0.27 mmol), catalytic dichlorobis(triphenylphosphine) palladium(II) and 0.297 mL of 1M aqueous sodium carbonate. The contents were heated at 150 degrees for 30 minutes in a microwave. The reaction was diluted with ethyl acetate and washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel using flash chromatography (gradient elution, ethyl acetate/hexane 0-50%). The material obtained (35 mg) after concentration of the fractions was purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A) to give 9 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 2.19-2.27 (m, 3H) 2.33 (s, 3H) 6.94-7.53 (m, 4H) 7.80 (d, J=9.52 Hz, 2H) 8.19-8.55 (m, 3H) 12.36 (s, 1H). MS (ESI+) m/z 333.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[CH:6]=[C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=4)[N:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccc(F)cc4o3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of methyl 2-(6-fluoro-1-benzofuran-2-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (78 mg, 0.19 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (23 mg, 0.57 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford (S)-2-(6-fluorobenzofuran-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid (37.3 mg, 52%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[N:16]=[C:15]([C:17]2[C:18]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[C:19]3[CH2:24][CH2:23][CH2:22][N:20]3[N:21]=2)[CH:14]=[CH:13][CH:12]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:11]1[N:16]=[C:15]([C:17]2[C:18]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[C:19]3[CH2:24][CH2:23][CH2:22][N:20]3[N:21]=2)[CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Brc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: c1ccc(Cc2cccc(-c3nn4c(c3-c3ccnc5ccccc35)CCC4)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Zinc(II) chloride (0.34 mL, 1.0 M solution, 0.34 mmol) is added, at room temperature with stirring, to a solution of benzyl magnesium chloride (0.15 mL, 2.0 M solution, 0.31 mmol) in tetrahydrofuran (1 mL). After 15 min, Pd(PPh3)2Cl2 (5.4 mg, 0.0076 mmol) is added followed by a solution of 4-[2-(6-bromo-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (60 mg 0.153 mmol) in tetrahydrofuran (1 mL). The reaction mixture is stirred for 18 h at room temperature and quenched with saturated aqueous ammonium chloride (1 mL). The reaction mixture is concentrated in vacuo, filtered, and the residue chromatographed on SiO2 (20-50% acetone/hexanes) to yield the title compound, 33.4 mg (54%), as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([O:19]C)=O)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:21])[O:4][N:3]=1.[CH:22]([Mg]Br)([CH3:24])[CH3:23]>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17](=[O:19])[CH:22]([CH3:24])[CH3:23])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: CC(C)[Mg]Br
Reactant: COC(=O)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(=O)C(C)C)c2[nH]c(=O)[nH]c2c1
Temperature: 25 °C

Procedure:
Methyl 6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (100 mg, 0.35 mmol) was dissolved in 5 mL of THF and stirred at room temperature followed by the addition of isopropylmagnesium bromide (0.87 mL, 2.0 mmol). Addition Grignard was added in 1 hour intervals until the starting material was consumed. Once complete, the crude reaction mixture was quenched with DI water and extracted 3× with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulphate, filtered, concentrated in vacuo, and purified via HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[C:3]=1[F:10].C(=[NH:24])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>CCOCC.C1COCC1.CCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].CCOC(C)=O>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:24]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)c(F)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc(F)cc(Br)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 164 %

Procedure:
A mixture of 1,3-dibromo-2,5-difluorobenzene (4 g, 14.7 mmol), benzophenone imine (2.6 mL, 15. 5 mmol), sodium tert-butoxide (2.1 g, 22.1 mmol), (S)-BINAP (1.4 g, 2.2 mmol), in toluene (15 mL) was sparged with Argon and charged with Pd2(dba)3 (0.67 g, 0.74 mmol). The reaction was then sealed and irradiated at 100° C. for 30 minutes in a microwave reactor. The reaction mixture was diluted with Et2O and stirred for 2 hours with a palladium scavenger (Siliabond DMT). The mixture was filtered through a plug of Celite and the collected filtrate was partitioned between diethyl ether and water, and the resulting layers separated. The organic portion was washed with water, brine, dried (MgSO4), and concentrated to afford a brown red solid. The solid was dissolved in THF (40 mL) and treated with aqueous 6.0 N HCl solution (25 ml, 150 mmol). The reaction was stirred for 1.5 hours at room temperature was partitioned between water and Et2O. The layers were separated and the aqueous portion was brought to a pH of 9 with aqueous 1.0 M NaOH solution. The basic aqueous layer was extracted diethyl ether (3×30 mL) the combined diethyl ether layers were washed with aqueous 1.0 M NaOH solution, water, brine, dried (MgSO4), concentrated. Purification by flash chromatography (SiO2, O-10% EtOAc in heptane) afforded 3-bromo-2,5-difluoroaniline (1.7 g, 8.2 mmol, 56%, trace benzophenone) as an orange solid: 1H NMR (400 MHz, CDCl3) δ 3.93 (br s, 2H) 6.43 (m, 1H) 6.62 (m, 1H).