Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:30]=[CH:29][C:10]([CH:11]=[CH:12][C:13]3[C:14](F)=[N:15][CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[N:33]=1.C1(C)C=CC=CC=1.C([O-])([O-])=[O:48].[K+].[K+]>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.CCO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH:11]=[CH:12][C:13]3[C:14](=[O:48])[NH:15][CH:16]=[C:17]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[N:33]=4)[CH:18]=3)=[CH:29][CH:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: CNc1nccc(Cl)n1
Reactant: CC1(C)OB(c2cnc(F)c(C=Cc3ccc(N4CCCCC4)cc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1nccc(-c2c[nH]c(=O)c(C=Cc3ccc(N4CCCCC4)cc3)c2)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
A 100 mL round-bottomed flask was charged with 3-(4-(piperidin-1-yl)styryl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (199 mg, 0.49 mmol), 4-chloro-N-methylpyrimidin-2-amine (146 mg, 1.016 mmol) and Pd(PPh3)4 (59 mg, 50.9 μmol). Then toluene (20 mL), EtOH (10 mL) and 2M aq. K2CO3 (1.53 mL, 3.05 mmol) were added and the reaction mixture was immersed in an oil bath at 120° C. for 1 h. The reaction mixture was partitioned between EtOAc (30 mL) and water (50 mL) and the organic layer was dried (MgSO4), filtered and concentrated and then quickly filtered through silica (MeOH/CH2Cl2 gradient). After evaporation of volatiles the residue was dissolved in dioxane (8 mL) and water (3 mL) and concentrated HCl (0.66 mL) was added. The reaction mixture was heated to 110° C. for 70 min and then evaporated. Purification by reverse phase preparative HPLC (eluting with aq. TFA/MeCN) gave the title compound (40 mg, 21%) as a yellow solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:13]([CH3:22])[CH2:14][CH2:15][C:16](N(OC)C)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:6]([N:13]([CH3:22])[CH2:14][CH2:15][C:16](=[O:17])[CH2:1][CH2:2][CH2:3][CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)CCN(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)CCN(C)Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Add butyllithium (12.3 ml (1.6 M solution in hexane), 19.6 mmol) to a stirred solution of 3-(benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide and anhydrous tetrahydrofuran (70 ml) at −40° C. under N2. Stir for 1 hr at −40° C. Quench the reaction with saturated ammonium chloride (25 ml), allow the reaction to reach room temperature and add saturated sodium bicarbonate. Extract with ethyl acetate, wash with brine and dry over sodium sulfate. Filter off and concentrate to give the crude product. Purify the compound by flash chromatography, eluting with 2% ethanol/0.2% ammonium hydroxide/chloroform to yield 2.41 g (81%) of 1-(benzyl-methyl-amino)-heptan-3-one: mass spectrum (ion spray) m/z=234 (M+1); 1H NMR (CDCl3) δ 7.31-7.24 (m, 5H), 3.5 (s, 2H), 2.74-2.7 (m, 2H), 2.64-2.60 (m, 2H), 2.41 (t, 2H), 2.19 (s, 3H), 1.59-1.51 (m, 2H), 1.35-1.28 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:17][NH:18][O:19][CH3:20]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:18]([CH2:17][C:16]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:14]([F:13])[CH:15]=2)[O:19][CH3:20])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(C)c(F)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 100 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluoro-4-methyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-C gave the title amide as white crystals (100% yield): mp 131° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 2.25 (3H, broad s, CH3), 3.69 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.39 (1H, s, CH), 7.0-7.03 (2H, m, aromatics), 7.13 (1H, m, aromatic). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.51; H, 5.60; N, 4.24.
Reaction SMILES: [Li]CCCC.[CH:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16].Br[CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[CH2:21]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:20][CH2:19][CH2:18][C:16]#[C:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]#[CH:6]
Reactant: C#CCCCCCCCC#C
Reactant: BrCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C#CCCCCCCCC#CCCCCOC1CCCCO1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
n-BuLi (4.86 mL of 2.5 M in hexanes, 12.16 mmol) was added dropwise to a −78° C. solution of undec-1,10-diyne (2.0 g, 13.51 mmol) in dry tetrahydrofuran/HMPA (105 mL, 6:1) under an argon atmosphere. After 30 min, the reaction mixture was warmed to −10° C. over 2 h and maintained at this temperature for 20 min, then re-cooled to −75° C. To this was added a solution of 2-(4-bromobutoxy)-tetrahydropyran (2.4 g, 10.14 mmol) in dry THF (15 mL). The resulting mixture was warmed to room temperature over 3 h, maintained at this temperature for 12 h, then quenched with sat. aq. NH4Cl (25 mL). After 20 min, the mixture was extracted with ether (2×125 mL). The combined ethereal extracts were washed with water (2×100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 5% EtOAc/hexanes as eluent to give 2-(pentadeca-5,14-diynyloxy)tetrahydropyran (1.97 g, 64%) as a colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.6; 1H NMR (400 MHz, CDCl3) δ 4.58 (t, J=2.5 Hz, 1H), 3.82-3.89 (m, 1H), 3.71-3.78 (m, 1H), 3.43-3.53 (m, 1H), 3.36-3.47 (m, 1H), 2.01-2.20 (m, 6H), 1.93 (t, J=2.5 Hz, 1H), 1.27-1.81 (m, 20H). Lit. ref: F. Slowinski; C. Aubert; M. Malacria Eur. J. Org. Chem. 2001: 3491.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[O:20][CH3:21])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A batch with 2,4-dichloro-5-fluoropyrimidine (200 mg; 1.20 mmol; Aldrich Chemical Company Inc.), (4-fluoro-2-methoxyphenyl)boronic acid (224 mg; 1.31 mmol; Aldrich Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0) (138 mg; 0.12 mmol) in 1,2-dimethoxyethane (3.6 mL) and 2 M solution of potassium carbonate (1.8 mL) was degassed using argon. The batch was stirred under argon for 16 hours at 90° C. After cooling the batch was diluted with ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 1:1) to give the desired product (106 mg; 0.41 mmol).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([C:17]1([O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[CH2:19][CH2:18]1)([CH3:16])[CH3:15]>O.C(OCC)(=O)C>[OH:13][C:14]([C:17]1([O:20][C@H:21]2[CH2:22][CH2:23][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:3][C:4](=[O:7])[O:5][N:48]=5)=[CH:39][CH:40]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:25][CH2:26]2)[CH2:18][CH2:19]1)([CH3:16])[CH3:15]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC3(C(C)(C)O)CC3)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC3(C(C)(C)O)CC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.092 g), sodium hydrogen carbonate (0.14 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-{[4-(trans-4-{[1-(1-hydroxy-1-methylethyl)cyclopropyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.049 g) was added and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 38 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.018 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.017 mL) were added, and the mixture was stirred at room temperature for 45 min. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.025 g, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5](O)=[O:6].Cl.[NH2:34][C:35]1([C:46]2[N:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5]([NH:34][C:35]1([C:46]2[N:47]=[CH:48][CH:49]=[CH:50][N:51]=2)[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38]1)=[O:6]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)c(F)c12
Reactant: CC(C)(C)OC(=O)N1CC(N)(c2ncccn2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncccn5)CN(C(=O)OC(C)(C)C)C4)cc(F)c3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (50 mg, 0.114 mmol) and tert-butyl 3-amino-3-(pyrimidin-2-yl)azetidine-1-carboxylate hydrochloride (35.9 mg, 0.125 mmol) in DMF (1 ml) in a 25 ml round-bottomed flask was added PyBop (77 mg, 0.148 mmol) and then triethylamine (0.032 ml, 0.228 mmol). The reaction mixture was stirred overnight, and then diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The crude product was then purified by column chromatography (2% methanol in chloroform) to afford tert-butyl 3-(3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzamido)-3-(pyrimidin-2-yl)azetidine-1-carboxylate. Yield: 40 mg (52.4%). LCMS: (ES+) m/z observed=572.2 (M+H)+ of 4-fluoro-5-(3-fluoro-2-methyl-5-(3-(pyrimidin-2-yl)azetidin-3-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide
Reaction SMILES: [C:1]([N:4]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=[O:3])[CH3:2].[C:26]1([N:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=[C:33]2[C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].C(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>[C:1]([N:4]1[C:16]2[C:11](=[CH:12][C:13]([C:44]3[CH:45]=[CH:46][C:41]([C:33]4[N:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)=[CH:42][CH:43]=3)=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]1[CH:25]=[CH:24][CH:23]=[CH:22][C:9]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)n1c2ccc3ccccc3c2c2cc(Br)c3ccccc3c21
Reactant: OB(O)c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)n1c2ccc3ccccc3c2c2cc(-c3ccc(-c4nc5ccccc5n4-c4ccccc4)cc3)c3ccccc3c21
Yield: 90.9 %

Procedure:
Following the above procedure, Suzuki coupling of 3.4 g of 7-acetyl-12-bromo-7H-dibenzo [a,g]carbazole and 3.8 g of 4-(1-phenyl-1H-benzo [d]imidazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.01 g of tetrakis(triphenylphosphine)palladium, 2.7 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 4.6 g of 7-acetyl-12-[4-(1-phenyl-1H-benzo[d]imidazol-2-yl)phenyl]-7H-dibenzo [a,g]carbazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:37]4[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(OC)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-methoxy-benzenesulfonyl chloride. Purity (ELSD, based on MW=591.7)=94%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9][C:8]=2[CH:24]=1>CO.O>[C:20]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH3:19])[O:12][C:10]1[NH:9][C:8]2[CH:24]=[C:4]([F:3])[C:5]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)=[CH:6][C:7]=2[N:11]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5ccc(C(=O)[O-])cc5)cc4)c(F)cc3[nH]2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Oc2nc3cc(-c4ccc(-c5ccc(C(=O)O)cc5)cc4)c(F)cc3[nH]2)cc1C(=O)O
Temperature: 70 °C

Procedure:
5 M aqueous NaOH (3 mL) was added to a solution of ethyl, 4′-{6-fluoro-2-[3-(methoxycarbonyl)-4-methylphenoxy]-1H-benzimidazol-5-yl}biphenyl-4-carboxylate (750 mg, 1.43 mmol) in MeOH (30 mL). The solution was diluted with water until cloudy and heated at 70° C. for 20 min. Volatiles were removed and the residue was-dissolved in 20 ml water and acidified with 2 N aqueous HCl. The precipitated white solid was filtered and dried to afford the title compound as a white solid. LC-MS: calculated for C28H19FN2O5 482.46, observed m/e 483.11 (M+H)+ (Rt 1.91/4.0 min). 1H NMR (500 MHz, CD3OD): δ 8.18-7.25 (m, 13H), 2.62 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3](C)[CH3:4].[NH2:9][C@H:10](C(O)=O)[C@H](CC)C.[NH2:18][C@H:19](C(O)=O)CC(C)C>>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][C:4]1[N:9]=[CH:10][NH:18][CH:19]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
with a total content of valine, isoleucine and leucine of 30.3%.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[F:16])(=O)C.O.[CH3:18][CH2:19][O:20]C(C)=O>>[Br:15][C:12]1[CH:11]=[C:10]([F:16])[C:9]([OH:8])=[C:14]([C:19](=[O:20])[CH3:18])[CH:13]=1
Reactant: CC(=O)Oc1ccc(Br)cc1F
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1cc(Br)cc(F)c1O
Temperature: 150 °C

Procedure:
AlCl3 (5.0 g, 38 mmol) was added in portions to 4-bromo-2-fluorophenyl acetate (5.8 g, 25 mmol). The mixture was heated at 150° C. for 3 h and then brought to ambient temperature. Water (ice-cold) was slowly added and then EtOAc. The resulting mixture was vigorously stirred and then the phases were separated and the water phase extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness to give the title compound (5.3 g). MS m/z (rel. intensity, 70 eV) 233 (M+, 55), 232 (M+, 56), 218 (98), 217 (bp), 161 (10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17].C1(C)C=CC=CC=1>C1COCC1.OS(O)(=O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([N:8]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]2[CH3:12])[CH:7]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 5-chloro-2-nitrophenylamine (200 mg, 1.15 mmol) and hexane-2,5-dione (326 μL, 2.78 mmol) in THF (3 mL) was added 1 drop of conc H2SO4. Toluene (3 mL) was then added and the reaction was allowed to stir at 120° C. overnight. At this time the reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography (50% EtOAc-hexane) afforded 73 mg (25%) of the title compound as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 7.96 (d, 1H, J=8.7 Hz), 7.59-7.54 (m, 1H), 7.39 (d, 1H, J=2.0 Hz), 5.92 (s, 2H), 1.97 (s, 6H);
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)C2)=NC=1CC.[CH2:33]([O:35][C@H:36]1[CH2:40][NH:39][CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[C:51]([C:58]([F:61])([F:60])[F:59])=[N:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)=[C:44]([CH2:62][CH3:63])[N:43]=1)[CH3:34]>>[CH2:33]([O:35][C@H:36]1[CH2:40][N:39]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[C:51]([C:58]([F:61])([F:60])[F:59])=[N:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)=[C:44]([CH2:62][CH3:63])[N:43]=1)[CH3:34]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.30, 2.45, 2.68, 3.48˜3.58, 3.77, 3.88, 4.04, 4.29, 4.94, 5.29, 6.56, 6.98, 7.56; IR (diffuse reflectance) 2974, 2350 (w), 2337 (w), 1921 (w), 1607, 1568, 1538 (s), 1477 (s), 1397, 1342, 1278 (s), 1239, 1192, 1175, 1137 (s) cm−1 HRMS (ESI) calcd for C24H29N6O2SF3+H1 523.2103. found 523.2108.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]#[N:21])[CH:14]=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](/[C:19](=[CH:11]/[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)/[C:20]#[N:21])[CH:14]=1
Reactant: N#CCc1cccnc1
Reactant: O=Cc1ccnc2ccccc12
Product: N#C/C(=C\c1ccnc2ccccc12)c1cccnc1
Yield: 29.6 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 3-pyridineacetonitrile (118 mg) through Method B (production step 3), to thereby yield the target product (yield: 76 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:16]O>>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:16])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccncc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cnccc1C
Yield: 94 %

Procedure:
A solution of 4-methylnicotinic acid (2.00 g, 14.6 mmol) and concentrated H2SO4 (4.66 mL, 87.6 mmol) in MeOH (50 mL) was heated at about 60° C. for about 16 h. The reaction was concentrated under reduced pressure then partitioned with EtOAc (150 mL) and saturated aqueous NaHCO3 (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a constant weight to afford methyl 4-methylnicotinate as a clear liquid (2.30 g, 94%): LC/MS (Table 2, Method a) Rt=1.67 min; MS m/z: 152 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([F:21])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:26](N(CC)CC)[CH3:27].[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36]>C(OCC)(=O)C.O1CCCC1>[CH2:26]([O:20][C:18](=[O:19])[C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[C:10]([C:11](=[O:13])[NH:36][CH2:35][C:34]([F:38])([F:37])[F:33])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:27]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cc(F)cc(C(=O)O)c1OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
7.96 g (25 mmol) of 2-benzyloxy-5-fluoroisophthalic acid monethyl ester in dissolved or suspended in 50 ml of dry ethyl acetate, 3.57 g (30 mmol) of thionylchloride is added and stirred for 1 hour at 50° C. The reaction solution is then evaporated to dryness under reduced pressure, the residue is evaporated twice with 50 ml of dichloromethane each and dissolved in 30 ml of dry tetrahydrofuran. This solution is mixed with 3.03 g (30 mmol) of triethylamine and then a solution of 2.97 g (30 mmol) of 2,2,2-trifluoroethylamine in 10 ml of dry tetrahydrofuran is instilled. It is stirred for 5 more hours at room temperature, the reaction solution is concentrated by evaporation to oil under reduced pressure, it is dissolved in 80 ml of ethyl acetate and shaken out twice with 10 ml of 1N hydrochloric acid each and once with 10 ml of water. The organic phase is dried on magnesium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. 7.25 g (18.15 mmol)=72.6% of the theoretical yield of the compound is obtained as an amorphous solid.