Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(O)C>[F:23][C:20]([F:21])([F:22])[C:19]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=[N:17][N:18]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A solution of 129 g (0.40 mol) of 1-(4-benzyloxyphenyl)-5-trifluoromethyl-1H-tetrazole in 900 mL 1:2 THF/ethanol was hydrogenated at ambient temperature over 6 g 10% Pd/C at 45 psi hydrogen for 12 h. The catalyst was removed by filtration through Celite®, the cake washed with ethanol, and the filtrate concentrated. The product was dissolved in ether, filtered through magnesium sulfate and concentrated. During concentration the product began to crystallize, as the product crystallized the mixture was flushed with hexanes to remove the ether. The resulting slurry was cooled to 0° C., aged 1 hr, filtered, and the cake washed with hexanes. The yield upon drying was 84.8 g (91.5%) of white crystalline 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol: 1H NMR (CDCl3) δ 5.6 (s, 1H), 7.07 (m, 2H), 7.35 (m, 2H). MS (EI) m/z 230. Anal. Calcd for C8H5F3N4O: C, 41.75; H, 2.19; F, 24.76; N, 24.34. Found: C, 41.76; H, 2.23; F, 24.53; N, 24.42. KF <0.1%.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([CH3:11])=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1ccc(N)cc1C(F)(F)F
Product: Cc1ccc(Nc2nc3ccccc3[nH]2)cc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-methyl-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp>265° C.). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][O:2]1.[CH:11](O)=[O:12]>>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH:11]=[O:12])=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: O=CO
Reactant: Nc1ccc2c(c1)COC2
Product: O=CNc1ccc2c(c1)COC2
Yield: 69 %

Procedure:
1,3-Dihydro-2-benzofuran-5-amine (300 mg, 2.2 mmol) was added to HCOOH (10 mL), and the reaction was stirred at reflux overnight. The reaction was concentrated, basified to pH=8 with sat Na2CO3, and extracted with EtOAc. Organics were washed with brine, dried (Na2SO4), and concentrated to give 250 mg (69%) of N-(1,3-dihydro-2-benzofuran-5-yl)formamide as a yellow oil.
Reaction SMILES: C(OC([NH:11][CH:12]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)C1C=CC=CC=1.[BrH:30]>C(O)(=O)C.CCOCC>[BrH:30].[NH2:11][CH:12]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC(CCc1ccccc1)S(=O)(=O)c1ccccc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC(CCc1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Method A: Z-Hph-α-SO2Ph (1.0 g, 2.44 mmol) was treated with 30% hydrogen bromide in acetic acid (5 mL). After 30 minutes, the mixture was diluted with ether (300 mL), filtered, washed with ether (2×30 mL), and dried in vacuo to give 0.74 g (86%) 1-amino-3-phenyl-1-phenylsulfonylpropane hydrobromide (HBr.Hph-α-SO2Ph). To a solution of Mu-PheOH (0.64 g, 2.3 mmol) in THF (15 mL) were added 4-methylmorpholine (0.302 mL, 2.3 mmol) and isobutyl chloroformate (0.312 mL, 2.3 mmol). The mixture was stirred for 10 minutes. HBr.Hph-α-SO2Ph (0.74 g, 2.1 mmol) was added, followed by 4-methylmorpholine (0.302 mL, 2.3 mmol). After 45 minutes, the mixture was diluted with ethyl acetate (30 mL), washed with 15 mL each of 1M HCl, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give 0.75 g (65%) of the product, Mu-Phe-Hph-α-SO2Ph.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].OS(O)(=O)=O.[CH3:23]O>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:9]([O:11][CH3:23])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-butoxy-4-nitrobenzoic acid (City Chemicals) (2.5 g, 10.5 mmol) in methanol (10 mL) were added concentrated H2SO4 (1 g, 10.5 mmol). The reaction mixture was heated at reluxing for 2 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, aqueous saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methyl 3-butoxy-4-nitrobenzoate as a brown oil (2.5 g, 95%).
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[OH-].[Na+:20]>CO>[Na+:20].[CH:1]([S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([CH3:18])[C:15]([NH-:17])=[O:16])=[CH:10][CH:9]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Nc1ccc([C@@H](C)C(N)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)S(=O)(=O)Nc1ccc([C@@H](C)C([NH-])=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2R)-2-{(4-[(Isopropylsulfonyl)amino]phenyl}propanamide (1) (500 mg, 1.85 mmol) was dissolved in CH3OH (15 mL). NORMEX 1N NaOH (1.85 mL, 1.85 mmol) was added by dripping and the resulting solution was left stirring at room temperature for 2 h. After solvent evaporation, water (3 mL) was added and the clear solution was frozen and then lyophilized to give (2R)-2-{4-[(isopropylsulfonyl]amino}phenyl)propanamide sodium salt (541 mg, 1.85 mmol) as pale yellow powder. Quantitative yield. [α]D25 (c=0.4, CH3OH): −11.75°; 1H-NMR (D2O) δ 7.32 (d, 2H, J=7 Hz), 7.15 (d, 2H, J=7 Hz), 3.82 (q, 1H, J=7 Hz), 3.35 (m, 1H), 1.54 (d, 3H, J=7 Hz), 1.35 (d, 6H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC[C@H](N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 45.4 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (42 mg, 45% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.20 (m, 2H), 8.10 (br s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.05 (d, J=9.1 Hz, 1H), 6.99 (s, 1H), 6.83 (br s, 1H), 4.52 (d, J=11.7 Hz, 1H), 4.04-3.96 (m, 1H), 3.91 (s, 3H), 3.37-3.18 (m, 3H), 2.87 (br s, 1H), 2.21-2.14 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 544 [C30H30C1N5O3+H]+; HPLC>99.0% (AUC), tR=10.76 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH:13]=O)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C@@H:11]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:12][CH2:13][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc([C@H](CC=O)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cc([C@H](CCN2CCOCC2)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid[(S)-1-(2-methanesulfonyl-pyridin-4-yl)-3-oxo-propyl]-amide (40 mg, 0.09 mmol) and morpholine (15 μL, 0.17 mmol) in dichloroethane (2 mL) was stirred for 30 minutes. The mixture was then acidified (pH=4) with acetic acid (9 μL, 0.2 mmol) and then sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added. After 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The oily residue was purified by silica gel chromatography using a gradient of 0-10% methanol in EtOAc. The solid material from the column was purified a second time by reversed-phase HPLC using a 20 minute gradient of 5-95% MeCN (0.1% TFA) in H2O (0.1% TFA) (flow rate=25 mL/minute). Desired fractions from the column was made basic with saturated aqueous sodium bicarbonate (2 mL), concentrated to half of the original volume and extracted with EtOAc (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.FC(F)(F)S(O[Si:21]([CH3:24])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1)=[CH2:13]
Reactant: CC(=O)c1ccc(-n2cncn2)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1ccc(-n2cncn2)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in CH2Cl2 at 0° C., were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl trifluoromethanesulfonate (8 g, 36 mmol) and the resultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9](CS([O-])(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)N1CCC(CS(=O)(=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 63.2 %

Procedure:
To a mixture of N-(ethoxycarbonyl)-piperidine-4-methanesulphonate (10 g) and 4-hydroxy benzaldehyde (5.8 g) in dry DMF (75 ml), K2CO3 (11 g) was added and the mixture was stirred at 80° C. for 12 h. At the end of this time, the reaction mixture was cooled, added water and extracted with EtOAc. The EtOAc extract was washed with 5% aqueous Na2CO3 solution followed by brine and dried over anhydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure to give 7 g (63.6%) of the title compound as a semi solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.5 g) (45-55% dispersion in oil was added to a solution of 1-(4-pyridyl)piperazine (0.9 g) in dry dimethylformamide (10 ml) at ambient temperature and stirred for 30 minutes. After this time, 4-fluoronitrobenzene (0.65 ml) was added slowly and the temperature raised to 70° C. The mixture was maintained at this temperature for 2 hours. The reaction mixture was then quenched by pouring into water and acidifying with aq 2N HCl solution to pH 1. The acidic layer was washed with diethyl ether and then basified with aq 2N.NaOH solution. The resulting precipitate was filtered, washed with water, dissolved in methanol, filtered through phase separator paper and evaporated to dryness. The resulting crude material was recrystallised from methanol/ether to give 1-(4-pyridyl)-4-(4nitrophenyl)piperazine (0.64 g) as an oil, NMR: (CDCl3) 3.61(q,8H), 6.58(d,2H), 6.81(d,2H), 8.16(d,2H), 8.33(bs,2H); MS: m/z 285 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1)[CH:11]=[CH:10]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of 2,6-dichloroquinoline (1.5 g, 7.6 mmol) in DMF (50 ml) was added tert-butyl piperazine-1-carboxylate (7.1 g, 38.1 mmol, 5 eq), and potassium carbonate (2.1 g, 15.1 mmol, 2 eq). The mixture was stirred for 4 hours at 140° C. and then quenched by the addition of water (300 ml) and then extracted with ethyl acetate (3×100 ml). The organic layers were combined, washed with saturated aqueous sodium chloride (3×300 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue. The crude material was purified by silica gel chromatography using 1-10% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford tert-butyl 4-(6-chloroquinolin-2-yl)piperazine-1-carboxylate as a light yellow solid (1.6 g, 61%). (ES, m/z): [M+H]+ 348; 1H NMR (300 MHz, DMSO): δ 8.03 (d, J=9.3 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.50-7.58 (m, 2H), 7.29 (d, J=9.3 Hz, 1H), 3.68-3.71 (t, J=5.1 Hz, 4H), 3.43-3.47 (t, J=4.5 Hz, 4H), 1.43 (s, 9H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.C([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30]1)(OC(C)(C)C)=O>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:38]3[CH:37]=[N:36][C:35]([N:32]4[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]4)=[N:40][CH:39]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cnc(N5CCNCC5)nc4)nc32)c1Cl

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 2-(4-Boc-piperazin-1-yl)pyrimidine-5-boronic acid pinacol ester using Suzuki coupling conditions as described in Example 1. The Suzuki coupling yielded the desired compound in its BOC protected form. The BOC protected intermediate was then treated with TFA in CH2Cl2 and purified by Silica gel column chromatography.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C@H:3]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=O.[NH2:16][C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:15][CH:2]([CH3:1])[C@H:3]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][NH:16][C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18]
Reactant: CC(C)[C@@H](C=O)OCOCC[Si](C)(C)C
Reactant: COC(=O)[C@H](C)N
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](C)NC[C@@H](OCOCC[Si](C)(C)C)C(C)C
Reaction time: 17 h

Procedure:
3-methyl-2-(S)-(2-trimethylsilylethyloxy)methyloxybutanal (1.0 eq) was stirred in methanol at room temperature with L-Alanine, methyl ester (0.8 eq; Bachem). Sodium cyanoborohydride (0.5 eq) was added to the solution, and the reaction was stirred for 17 hours. The reaction was made alkaline by addition of aqueous saturated NaHCO3 solution. The mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via radial chromatography using 20% ethyl acetate in hexanes to afford the title intermediate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CC(C)([O-])C.[K+].[C:16]1(=[O:20])[O:19][CH2:18][CH2:17]1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:18][CH2:17][C:16]([OH:20])=[O:19]
Reactant: O=C1CCO1
Reactant: Cc1ccc(F)c(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(F)c(OCCC(=O)O)c1
Temperature: 25 °C
Yield: 60759.5 %

Procedure:
To a suspension of 2-fluoro-5-methylphenol (1.0 g, 7.9 mmol) in tetrahydrofuran (10 mL) at 0-5° C. was dropwise added potassium tert-butoxide 1N in tetrahydrofuran (8.3 mL, 8.3 mmol), followed by 3-propiolactone (0.55 mL, 8.7 mmol) in one portion. The mixture was warmed to room temperature for 1 hour, then heated at 50° C. for 2 hours. After cooling to room temperature, the mixture was quenched with a saturated solution of sodium hydrogenocarbonate (1 mL) and diluted with water (9 mL). The aqueous layer was washed with ethyl acetate (10 mL), acidified with 1M hydrochloric acid until pH 2 and extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 3-(2-fluoro-5-methylphenoxy)propanoic acid (10a) (0.96 g, 4.8 mol, 60%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][NH:50][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=NCCN4)cc3)co2)c(C)c1
Temperature: 25 °C

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (100 mg, 0.3 mmol) was dissolved in DCE (6 mL) and CDI (195 mg, 0.6 mmol) was added. The reaction was stirred at room temperature until complete as determined by LCMS. 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethanamine (54 mg, 0.3 mmol) and DIPEA (0.63 mL, 1.8 mmol) was added and the reaction stirred for 4 days. The reaction was washed with saturated aqueous NH4Cl (6 mL) and the aqueous wash extracted with DCE (3×6 mL). The combined organic extracts were dried over MgSO4 and the solvent removed in vacuo. The resulting crude product was purified using prep method B to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[Si:29]([C:33]#[CH:34])([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C.N#N>CN(C=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.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:34]#[C:33][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 59.5 %

Procedure:
A solution of (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (5.00 g, 11.1 mmol), TMS-acetylene (7.90 mL, 55.5 mmol) and triethylamine (4.64 mL, 33.3 mmol) in DMF (56 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (1.28 g, 1.11 mmol) and CuI (106 mg, 0.56 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (10-80% EtOAc-hexanes gradient) to afford (2-methyl-1-{2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (3.08 g, 6.60 mmol, 59% yield). LCMS-ESI+: calc'd for C25H35N4O3Si: 467.3 (M+H+). Found: 467.1 (M+H+).