Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[C:3]([NH:6][C:7]1[C:8]([I:33])=[C:9]([C:24]([N:26]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH3:27])=[O:25])[C:10]([I:23])=[C:11]([C:21]=1[I:22])[C:12]([N:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH3:15])=[O:13])(=[O:5])[CH3:4].B(O)(O)O.[O:38]1[CH2:40][CH:39]1[CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH:47]1[CH2:49][O:48]1.Cl>C(#N)C.O.O.CO>[OH:38][CH:39]([CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH:47]([OH:48])[CH2:49][N:6]([C:7]1[C:21]([I:22])=[C:11]([C:12]([N:14]([CH3:15])[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:13])[C:10]([I:23])=[C:9]([C:8]=1[I:33])[C:24]([N:26]([CH3:27])[CH2:28][CH:29]([OH:32])[CH2:30][OH:31])=[O:25])[C:3](=[O:1])[CH3:4])[CH2:40][N:6]([C:7]1[C:21]([I:22])=[C:11]([C:12]([N:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH3:15])=[O:13])[C:10]([I:23])=[C:9]([C:8]=1[I:33])[C:24]([N:26]([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH3:27])=[O:25])[C:3](=[O:5])[CH3:4]
Reactant: C(COCC1CO1)OCC1CO1
Reactant: [OH-]
Reactant: CC(=O)Nc1c(I)c(C(=O)N(C)CC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC(=O)N(CC(O)COCCOCC(O)CN(C(C)=O)c1c(I)c(C(=O)N(C)CC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I)c1c(I)c(C(=O)N(C)CC(O)CO)c(I)c(C(=O)N(C)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 5 %

Procedure:
To a stirred solution of water/methanol (4.9 ml, 2.5 ml) and potassium hydroxide (0.47 g, 8.4 mmol) at 40° C. was added 5-acetylamino-N,N′-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo-N,N′-dimethyl isophthalamide (5.0 g, 6.5 mmol). To the clear solution was then added boric acid (0.28 g, 4.5 mmol). The mixture was cooled to room temperature and pH adjusted to 12.6. 2-{[2-(oxiran-2-ylmethoxy)-ethoxy]methyl}oxirane (0.382 g, 2.22 mmol) was added. The pH of the solution was adjusted to the interval 12.6-13. The reaction was left over weekend. To the solution was added HCl (18%) to pH 4. Salts were removed by treatment with ion exchanger AMB200C and IRA67. The solution was filtered from the resin and evaporated. The product was purified by preparative HPLC (column YMC amino 21.2×250 mm, solvents: A=water and B=acetonitrile; gradient 85-65% B over 25 min; flow 25.0 ml/min, UV detection at 214 nm and 254 nm), and obtained in 180 mg after lyophilisation, 5% yield. Analysis by LC-MS (column Agilent Zorbax SB-Aq 3.5 μm 3.0×100 mm, solvents: A=water/0.1% formic acid and B=acetonitrile/0.1% formic acid; gradient 0-30% B over 20 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS) gave one broad peak centred at 9.6 minutes with m/z 1724.6 (MH+) corresponding to the structure.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([CH2:18][OH:19])[C:11]=2[OH:20])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].C(OCC)C>C1COCC1>[C:28]([O:19][CH2:18][C:12]1[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]([N:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1]2)[C:11]=1[OH:20])(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccccc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccccc3n2)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 4.03 g (14.9 mmol) 2-(2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol in 50 ml anhydrous THF. Triethylamine (7.4 ml, 53 mmol) was added and the mixture was cooled to −10° C. Methacryloyl chloride (1.99 g, 19.0 mmol) was added dropwise and the mixture was stirred for 1 hr at 0° C. followed by 6 hours at ambient temperature. The mixture was poured into 200 ml diethyl ether and washed with 0.5 N HCl and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated via rotary evaporation to give the desired product as a dark yellow oil which was recrystallized in methanol to give 1.73 g of a light yellow solid (34%). 1H NMR (CDCl3) delta: 11.26 (s, 1H, Ar—OH), 7.92 (d, 2H, Ar—H benzotriazole), 7.91 (s, 1H, Ar—H meta to phenol), 7.49 (d, 2H, Ar—H benzotriazole, 5,6-position), 7.05 (s, 1H, Ar—H meta to phenol), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.40 (s, 2H, Ar—CH2), 3.90 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[C:10]([Cl:20])=[CH:11][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:21][C:22]([S@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:22]([S@:25]([N:27]=[C:1]([C:4]1[N:9]=[C:8]2[C:10]([Cl:20])=[CH:11][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:7]2=[CH:6][CH:5]=1)[CH3:2])=[O:26])([CH3:24])([CH3:23])[CH3:21].[C:22]([S@:25]([N:27]=[C:1]([C:4]1[N:9]=[C:8]2[C:10]([Cl:20])=[CH:11][N:12]([C:13]([O:15][CH2:16][CH3:19])=[O:14])[C:7]2=[CH:6][CH:5]=1)[CH3:2])=[O:26])([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(=O)c1ccc2c(n1)c(Cl)cn2C(=O)OC(C)(C)C
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(=N[S@](=O)C(C)(C)C)c1ccc2c(n1)c(Cl)cn2C(=O)OC(C)(C)C
Product: CCOC(=O)n1cc(Cl)c2nc(C(C)=N[S@](=O)C(C)(C)C)ccc21
Temperature: 75 °C
Reaction time: 16 h
Yield: 29.88 %
Yield: 56.59 %

Procedure:
To tert-butyl 5-acetyl-3-chloro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2.90 g, 9.84 mmol) and (R)-2-methylpropane-2-sulfinamide (1.79 g, 14.76 mmol) dissolved in anhydrous THF (96 mL) was added titanium (IV) ethoxide (5.16 mL, 24.60 mmol) at RT under N2. The reaction mixture was then stirred at 75° C. under N2 for 16 h. Volatile solvent was removed under reduced pressure, and the crude residue was diluted with EtOAc (−250 mL). The reaction mixture was vigorously stirred while a saturated solution of brine (−40 mL) was slowly added. The reaction mixture was stirred for 15 min and filtered through a pad of Celite®. The organic layer from the filtrate was washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with EtOAc/heptane to afford 1.17 g (29.88%) of (R)-tert-butyl 5-(1-((tert-butylsulfinyl)imino)ethyl)-3-chloro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate and 2.06 g (56.59%) of (R)-ethyl 5-(1-((tert-butylsulfinyl)imino)ethyl)-3-chloro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16](O)=[O:17])[C:9]2=[O:19].C([N:22](CC)CC)C.ClC(OCC)=O.CN(C)CCN>CN(C)C=O.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]([C:16]([NH2:22])=[O:17])[C:9]2=[O:19]
Reactant: COCCOc1ccc2[nH]cc(C(=O)O)c(=O)c2n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN(C)CCN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1ccc2[nH]cc(C(N)=O)c(=O)c2n1
Reaction time: 1.25 h

Procedure:
To a solution of 6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (106 mg, 0.4 mmol) and triethylamine (117 mL, 0.84 mmol) in 4:1 tetrahydrofuran: N,N- dimethylformamide (2 mL) at 0° C. was added ethyl chloroformate (66 mL, 0.82 mmol). After stirring at O C for 1.25 h, 4-[(N-tert-butoxycarbonyl)-methylaminomethyl)benzylamine hydrochloride (120 mg, 0.42 mmol) and triethylamine (59 mL, 0.42 mmol) was added. The reaction mixture was stirred at 0° C. for 0.75 h, then allowed to ambient temperature and stirred for 20 h. N,N-Dimethylethylenediamine (132 mL, 1.2 mmol) was added, the reaction mixture stirred for 1 h, then concentrated in vacuo. The residue was cooled in an ice bath, saturated aqueous ammonium chloride was added and the mixture extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated to give 177 mg of crude N-[4-(N-tert butoxycarbonyl)-methylaminomethyl)benzyl] 6-(2-methoxyethoxy)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li+].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.CI.O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([N:16]([CH3:24])[S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)S(=O)NC(c1ccccc1)c1cc(Br)ccc1N
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(c1ccccc1)c1cc(Br)ccc1N)S(=O)C(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 2-Methyl-propane-2-sulfinic acid [(2-amino-5-bromo-phenyl)-phenyl-methyl]-amide (60 g, 157 mmol) in DMF (700 mL) is cooled to −20° C., then LiHMDS (163 mL, 173 mmol) is added dropwise. After the addition the mixture is stirred at −20° C. for 1 h. Then CH3I (22.3 g, 157 mmol) is added dropwise. After the addition the mixture is warm to r.t. for 2 h. Then H2O is added and is was extracted with MeO(CH3)3, dried over Na2SO4 and concentrated to give product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.ClC(N(C)C)=C(C)C.[Br:45][C:46]1[C:47]([F:53])=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:49][C:48]1[CH:50]=[CH:51][CH:52]=[C:46]([Br:45])[C:47]=1[F:53])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(Br)c1F
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Agent: CC(C)=C(Cl)N(C)C
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1[C@@H](C(=O)Nc2cccc(Br)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Reaction time: 2 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described in Scheme B25, 100 mg, 0.380 mmol) in CH2Cl2 (2.4 mL) at 0° C. under nitrogen atmosphere was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (50.8 mg, 0.38 mmol) and the mixture was stirred at this temperature for 2 h. 3-Bromo-2-fluoroaniline (144 mg, 0.76 mmol) was then added, followed by DIPEA (0.265 mL, 1.52 mmol) and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 μm, 30×100 mm, eluent: 0-0.5 min 5% CH3CN in H2O Flow: 5 mL/min, 0.5-18.5 min 5 to 100% CH3CN/H2O Flow: 40 mL/min, 18.5-20 min 100% CH3CN, CH3CN and H2O both containing 0.1% TFA). The purified HPLC fractions were neutralized by addition of a saturated aqueous solution of Na2CO3, the layer were separated and the aqueous layer was extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. White solid. Rf, TLC (c-hexane/EtOAc 1:1)=0.75; MS (UPLC): 435.1/437.1 [M+H]+, 433.1/435.1 [M−H]−; tR (HPLC conditions f): 2.06 min.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C@H:14]2[O:20][C@H:18]([OH:19])[C@H:17]([OH:21])[C@@H:16]([OH:22])[C@@H:15]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].S([O-])([O-])(=O)=O.[Ca+2].[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:30]([O:11][CH2:10][C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@H:14]2[O:20][C@H:18]([OH:19])[C@H:17]([OH:21])[C@@H:16]([OH:22])[C@@H:15]2[OH:23])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@H:6]1[OH:7])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](CO[C@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H](O)[C@H](O)[C@H]2O)[C@H]1O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 5.13 g portion of anhydrous 6-O-α-D-galactopyranosyl-α-D-glucopyranose is suspended in 50 ml of pyridine and 5.0 g of anhydrous calcium sulfate is added. This mixture is heated at 90° C. for 30 minutes, then 4.6 g of trityl chloride is added and heating and stirring are continued for 2 hours. The solution is cooled to room temperature, 10 ml of acetic anhydride is added and the mixture is allowed to stand overnight. The mixture is poured into crushed ice and the solid is filtered, washed with water and dried, giving 10 g of 6-O-(6-O-trityl-α-D-galactopyranosyl)-α-D-glucopyranose, heptaacetate as a colorless granular solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[C:49]1([CH2:55][CH2:56][CH2:57]Br)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O>[CH:8]1([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)[N:21]([CH2:34][CH2:35][CH2:36][CH:37]4[CH2:38][CH2:39][N:40]([CH2:57][CH2:56][CH2:55][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[CH2:41][CH2:42]4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: BrCCCc1ccccc1
Reactant: Clc1ccc(OCc2nc3c(OCC4CCCCC4)cccc3n2CCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OCc2nc3c(OCC4CCCCC4)cccc3n2CCCC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 4-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting mixture was stirred at 80° C. for six hours. The reaction was quenched by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3×10 ml). The organic fractions were combined, washed with water (3×10 ml), and brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CC1C=CC=C(C)N=1.[Si:41]([O:48][CH2:49][C@@H:50]1[C@@H:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:53][NH:52][CH2:51]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:1][C@@H:2]([CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].[Si:41]([O:48][CH2:49][C@@H:50]1[C@@H:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:53][N:52]([C@H:2]([CH2:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:51]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Agent: O=C(OCc1ccccc1)[C@@H](O)CC1CCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of 1.84 g (7.8 mmol) of 2-(S)-hydroxy-3-(cyclobutyl)propionic acid, benzyl ester (Hydroxy Ester 2) in 30 mL of CH2Cl2 at −5° C. was treated with 1.40 mL (8.4 mmol) of trifluoromethanesulfonic anhydride maintaining the internal temperature at less than 0° C. The resulting mixture was stirred cold for 2 min, then treated with 1.10 mL (9.6 mmol) of 2,6-lutidene, maintaining the internal temperature at less than 0° C. The resulting mixture was stirred cold for 30 min, then treated with a solution of 2.65 g (9.5 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)4-(S)-phenylpyrrolidine (Pyrroldine 1) in 10 mL of CH2Cl2 and 3.00 mL (31.2 mmol) of DIEA. The resulting mixture was warmed to rt and stirred for 20 h. The reaction was quenched with 50 mL of sat'd NaHCO3 and the quenched mixture was extracted with 200 mL of ether. The ether extract was dried over MgSO4 and concentrated. Flash chromtography on 150 g of silica gel using 20:1 v/v hexanes/ether as the eluant afforded 3.23 g (81% based on Hydroxy Ester 2) of the title compound: 1H NMR (300 MHz) δ−0.25 (s, 3H), −0.21 (s, 3H), 0.84 (s, 9H), 1.57-2.07 (8H), 2.29-2.39 (2H), 2.66-2.77 (m, 2H), 2.93 (q, J=7.8, 1H), 3.06 (t, J=8.4, 1H), 3.19 (t, J=8.4, 1H), 3.26 (dd, J=2.1, 6.3, 1H), 3.45-3.60 (m, 2H), 5.15 (s, 2H), 7.17-7.38 (10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[C:7]([C:8]([N:39]2[C:40]3[C:35](=[CH:34][C:33]([CH3:32])=[CH:42][CH:41]=3)[CH2:36][CH2:37][CH2:38]2)=[O:10])=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1ccc(F)c(Cl)c1
Temperature: 140 °C
Yield: 7.8 %

Procedure:
A solution of 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (32.1 mg, 0.12 mmol, 1.0 equiv) in thionyl chloride (57 mg, 35 pt, 0.48 mmol, 4.0 equiv; [CAS RN 7719-09-7]) was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (77.6 mg, 102 μL, 0.60 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 6-methyl-1,2,3,4-tetrahydro-quinoline (21.2 mg, 0.14 mmol, 1.2 equiv; [CAS RN 91-61-2]) and the reaction mixture heated by microwave irradiation to 140° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 auto sampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 3.7 mg (8%) of the title compound. MS (ISP): 397.0 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl.[CH3:11]O>>[CH3:11][O:8][C:7](=[O:9])[C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Reaction time: 16 h

Procedure:
A suspension of 4(R)-hydroxyproline (35.12 g, 267.8 mmol) in methanol (500 ml) was saturated with gasseous hydrochloric acid. The resulting solution was allowed to stand for 16 hrs and the solvent evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:34]([Cl:35])=[CH:33][C:17]3[NH:18][C:19]([O:21][C:22]4[CH:23]=[CH:24][C:25]([CH3:32])=[C:26]([CH:31]=4)[C:27]([O:29][CH3:30])=[O:28])=[N:20][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.[F:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O1CCOCC1.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>[Cl:35][C:34]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([F:36])[CH:42]=3)=[CH:9][CH:10]=2)=[CH:15][C:16]2[N:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:32])=[C:26]([CH:31]=3)[C:27]([O:29][CH3:30])=[O:28])[NH:18][C:17]=2[CH:33]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(Br)cc4)c(Cl)cc3[nH]2)ccc1C
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: C1COCCO1
Product: COC(=O)c1cc(Oc2nc3cc(-c4ccc(-c5cccc(F)c5)cc4)c(Cl)cc3[nH]2)ccc1C

Procedure:
K2CO3 (1 M in water) (0.16 mL, 0.162 mmol) was added to a solution of methyl 5-{[5-(4-bromophenyl)-6-chloro-1H-benzimidazol-2-yl]oxy}-2-methylbenzoate (25.5 mg, 0.054 mmol), 3-fluorophenylboronic acid (9 mg, 0.068 mmol) and Pd(PPh3)4 (6 mg) in dioxane (1 mL). The reaction was microwaved at 150° C. for 8 minutes. Volatiles were removed. The residue was partitioned between EtOAc (50 mL), and water (50 mL). The aqueous phase was extracted with EtOAc (3×40 mL). Combined organics were washed with brine, dried (MgSO4), filtered and concentrated. Purification by HPLC eluting with 10-90% MeCN:water afforded the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([CH2:2][C:3]2[N:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cnc(CBr)cn1
Reactant: C1CCNC1
Product: COC(=O)c1cnc(CN2CCCC2)cn1
Yield: 85 %

Procedure:
By essentially following the procedure used to prepare Example 137, Part B, the title compound was prepared from methyl 5-(bromomethyl)pyrazine-2-carboxylate (Part A) and pyrrolidine in 85% yield as a pale yellow oil. The mixture was subjected to flash chromatography on silica gel, eluting with a gradient of EtOAc(100-95%)/Et3N(0-5%).
Reaction SMILES: [C:1]1([CH:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19]O.[CH:21](O)([CH3:23])C>>[C:5]1([CH2:6][C:1]2[CH:7]=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[O:18][N:19]=2)[CH:4]=[CH:3][CH:2]=[CH:23][CH:21]=1
Reactant: NO
Reactant: CC(C)O
Reactant: CC(=O)C(C(=O)c1cccnc1)c1ccccc1
Product: c1ccc(Cc2cc(-c3cccnc3)on2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of phenylnicotinoyl acetone 0.500 g (0.0021 mol), isopropyl alcohol (5 ml) and hydroxylamine free base (in 7 ml methanol) was stirred at room temperature for 3 days (72 hrs.). The reaction mixture was concentrated to dryness and purified by column chromatography using a mixture of ethylacetate and hexanes (3:1). The purified compound (oxime) was dissolved in IPA (10 ml) and to it was added 2 N HCl (4 drops). The reaction mixture was refluxed for 8 hrs. The reaction mixture is finally concentrated to dryness to yield the desired compound as a pale yellow solid: