Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[C:13]=3[C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]#[N:33].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].CN(C=O)C.Cl>O>[Br:1][C:2]1[C:3]([O:30][CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([C:12]1[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13]=1[C:21](=[O:29])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:7]2
Reactant: N#CCOc1ccc2cc(-c3sc4ccccc4c3C(=O)Cc3ccccc3)ccc2c1Br
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)c1c(-c2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)sc2ccccc12
Temperature: 80 °C
Yield: 38 %

Procedure:
A mixture of [1-bromo-6-(3-phenylacetyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetonitrile (0.437 g, 0.852 mmol), sodium azide (0.284 g, 4.36 mmol) and ammonium chloride (0.233 g, 4.36 mmol) in DMF (10 mmol) was heated at 80° C. for two hours. After cooling to ambient temperature, the reaction mixture was poured into excess water and acidified with 2N hydrochloric acid. This was then extracted with ethyl acetate. The organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by HPLC using 72% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 64° C. for four hours yielded 1-{2-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-benzo[b]thiophen-3-yl}-2-phenyl-ethanone as a yellow foam (0.180 g, 38.1%); mass spectrum (+EI, [M+H]+) m/z 555/557. 1H NMR (500 MHz, DMSO-d6): δ16.7–17.2 (br, 1H), 8.27 (d, 1H, J=8.86 Hz), 8.18–8.20 (m, 2H), 8.07–8.10 (m, 1H), 7.90–7.93 (m, 1H), 7.82 (dd, 1H, J=8.70 Hz and 1.83 Hz), 7.77 (d, 1H, J=9.16 Hz), 7.45–7.50 (m, 2H), 7.13–7.19 (m, 3H), 6.93 (dd, 2H, J=7.64 Hz and 1.55 Hz), 5.77 (s, 2H), 3.81 ppm (s, 2H). Elemental Analysis for C28H19BrN4O2S+0.3 mole H2O: Calcd: C, 59.96; H, 3.52; N, 9.99; Found: C, 59.58; H, 3.40; N, 9.69.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].[NH2:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([Cl:18])[N:12]=1.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[NH2:10][C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH:2]2[C:7]([NH2:9])=[O:8])[CH:14]=[C:13]([Cl:18])[N:12]=1
Reactant: NC(=O)C1COCCN1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1COCCN1c1cc(Cl)nc(N)n1
Temperature: 100 °C
Reaction time: 40 h
Yield: 50 %

Procedure:
A mixture of 3-morpholinecarboxamide (830 mg, 3.40 mmol), 2-amino-4,6-dichloropyrimidine (502 mg, 3.06 mmol), and Hunig's base (1.6 mL, 9.16 mmol) in CH3CN (12 mL) was stirred at 100° C. in a sealed tube for 40 hours. The mixture was diluted with EtOAc (100 mL), and washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL). The combined aqueous phases were further extracted with CH2Cl2 (3×50 mL) and EtOAc (3×50 mL). All of the organic phases were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (34 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (394 mg) as a white solid. LC-MS (ES) m/z=258, 260 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[N:20]1[NH:21][N:22]=[N:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:32][CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:20]=[N:21][NH:22][N:23]=2)=[CH:30][CH:29]=1)=[O:9]
Reactant: NCc1ccc(-c2nn[nH]n2)cc1
Reactant: O=C(O)c1cc(F)ccc1Oc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NCc1ccc(-c2nn[nH]n2)cc1)c1cc(F)ccc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A mixture of 5-fluoro-2-(4-fluorophenoxy)benzoic acid (120 mg, 0.48 mmol), 1-[4-(2H-tetrazol-5-yl)phenyl]methanamine hydrochloride (122 mg, 0.58 mmol), 1-hydroxy-1H-benztriazole monohydrate (110 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol), and triethylamine (0.27 mL, 1.92 mmol) in dichloromethane (8 mL) and N,N-dimethylforamide (2 mL) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane (50 mL) and washed with 5% aqueous sodium dihydrogenphosphate solution (30 mL). The organic fraction was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate/acetic acid (30:60:1) to afford 143 mg (73%) of the title compounds as white solids: 1H-NMR (DMSO-d6) δ 8.99 (1H, t, J=5.9 Hz), 7.91 (2H, d, J=8.2 Hz), 7.53–6.99 (8H, m), 4.50 (2H, d, J=5.9 Hz); MS (ESI) m/z 408 (M+H)+, 406 (M−H)−.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:37](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:35]=[CH:34][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([OH:32])=[S:37])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
2.2 g (20 mmol) of triethylamine and a solution of 1.4 ml (10 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise in succession to a solution, cooled to -10°, of 2.82 g (10 mmol) of 4-p-nitrobenzyloxycarbonylaminobutyric acid in 50 ml of dry methylene chloride. The reaction mixture is stirred for one hour and subsequently a strong current of hydrogen sulphide is passed through for a period of 2 hours. After acidifying with 2N sulphuric acid, the organic phase is separated, dried and concentrated in vacuo. The 4-p-nitrobenzyloxycarbonylaminothiobutyric acid obtained can be used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([F:39])[C:8]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:7]([CH:18]2[O:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)COC(c2ccc(C(C)(C)C)cc2C2OCCCO2)=N1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Temperature: -17 °C
Reaction time: 3 h
Yield: 33.1 %

Procedure:
To a solution of 101e (20 g, 63 mmol) in anhydrous THF (400 mL) was added 2.4 M solution of n-butyllithium in hexane (65 mL) at −78° C. under N2 atmosphere. The clear yellow solution was stirred at −17° C. for 3 hr, when it showed a deep red-orange color. The reaction solution was re-cooled to −78° C., stirred rapidly and a solution of N-fluorobenzenesulfonimide (29 g, 92 mmol) in anhydrous THF (100 mL) was added in dropwise over 10 min. The reaction mixture was stirred at −78° C. for 5 min, −20° C. for 30 min, then room temperature for 1 h. The reaction mixture was poured into 150 mL of 50% aqueous NH4Cl and extracted with 300 mL of EtOAc. The separated organic phase was washed with 150 mL of water and 150 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by silica gel chromatography using EtOAc/CH2Cl2=1:5 as eluent to afford 101f (7 g, 33%) as yellow solid. LCMS (ESI) m/z 336 (M+H)+. 1HNMR (300 MHz, CDCl3) δ 7.53 (d, J=1.6 Hz, 1H), 7.08 (dd, J=2.0, 12.0 Hz, 1H), 5.90 (s, 1H), 4.24 (dd, J=5.2, 10.8 Hz, 2H), 4.06 (s, 2H), 3.98-3.91 (m, 2H), 2.26-2.19 (m, 1H), 1.45-1.42 (m, 1H), 1.42 (s, 6H), 1.30 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(=[NH:35])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>[NH2:35][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of (2S)-2-(4-bromophenyl)-4-((1R)-l-phenylethyl)morpholine (15.6 g, 45 mmol), benzophenone imine (9 g, 50 mmol), tris(dibenzylideneacetone)-dipalladium(0)-chloroform adduct (0.93 g, 0.9 mmol), sodium tert-butoxide (6.0 g, 63 mmol) and 2-(di-t-butylphosphino)biphenyl (0.53 g, 1.8 mmol) in toluene (135 ml) was stirred at 95° C. for 4 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. To a solution of the resulting residue in tetrahydrofuran (180 ml) was added 6N hydrochloric acid (180 ml) and the mixture was stirred at room temperature for one hour. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by column chromatography on silica gel (hexane-AcOEt, 2:1) to give (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (12.2 g, 96%) as an oil.
Reaction SMILES: B(Br)(Br)Br.C[Sn](C)(C)C.COCCOC[O:16][CH:17]([C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[S:27])=[O:26])[S:22][C:23]=1[CH3:24])[CH3:18].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)CCC>[OH:16][CH:17]([C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[S:27])=[O:26])[S:22][C:23]=1[CH3:24])[CH3:18]
Reactant: COCCOCOC(C)c1cc(S(N)(=O)=S)sc1C
Agent: BrB(Br)Br
Agent: C[Sn](C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCCCCl
Product: Cc1sc(S(N)(=O)=S)cc1C(C)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To boron tribromide (40 ml of a 1.0M solution in methylene chloride) cooled under a nitrogen atmosphere to -50° C. was added dropwise over 1/2 hour tetramethyl tin (7.15 g, 0.04 mol). The resulting solution was stirred for 1/2 hour at -50° C. and then for 1/2 hour at 15° C. The solution was cooled to -78° C. and 4-[1-(methoxyethoxymethoxy)ethyl]-5-methylthiothiophene-2-sulfonamide (3.41 g, 0.01 mol) in methylene chloride (15 ml) was added dropwise over 15 minutes. The mixture was stirred at -78° C. for 3/4 hour and then poured into saturated NaHCO3 solution. Some additional solid NaHCO3 was added and the basic mixture was filtered. The filtrate was extracted with ethyl acetate (2×100 ml). The ethyl acetate solution was extracted with 0.5M KOH solution (2×100 ml). The KOH extracts were washed with ether and acidified with 6N HCl. The acidified mixture was extracted with ethyl acetate (2×50 ml). This extract was washed with saturated NaHCO3, water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at ambient temperature. A pale amber oil was obtained (1.5 g). NMR confirmed the structure. After trituration in n-butyl chloride the oil solidified. Recrystallization from 1,2-dichloroethane gave 0.54 g (21%) of white solid, m.p. 100-102° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[C:13]1[C:14]([F:34])=[C:15]([N:19]([CH2:31][O:32][CH3:33])[S:20]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.CO[CH2:46][CH2:47]OC.O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[S:20]([N:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:3]2[N:4]=[C:5]([CH:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[S:6][C:2]=2[C:47]2[CH:46]=[CH:31][N:19]=[CH:15][C:14]=2[F:34])[C:14]=1[F:34])[CH2:31][O:32][CH3:33])(=[O:22])=[O:21]
Reactant: COCCOC
Reactant: COCN(c1cccc(-c2nc(C3CCOCC3)sc2Br)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COCN(c1cccc(-c2nc(C3CCOCC3)sc2-c2ccncc2F)c1F)S(=O)(=O)c1cc(F)ccc1F
Reaction time: 0.5 h

Procedure:
N-{3-[5-bromo-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (105 mg, 0.182 mmol) was dissolved in a microwave tube in a 9:1 DME/H2O mixture (2.2 mL) and argon was bubbled through the solution for 5 min. Cesium carbonate (148 mg, 0.454 mmol, 2.5 eq) was added, followed by 3-F-4-pyridineboronic acid pinacol ester (82 mg, 0.368 mmol, 2 eq) and Pd(dppf)Cl2.DCM (15 mg, 0.018 mmol, 0.1 eq) and the mixture was irradiated in the microwave oven at 100° c. for 30 min. An addition of Pd(dppf)Cl2.DCM (15 mg, 0.018 mmol, 0.1 eq) was made and the mixture underwent a second microwave cycle. The mixture was filtered through a celite pad and the celite was washed thoroughly with ethyl acetate. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatograpy on silica gel to give 76 mg of 2,5-difluoro-N-{2-fluoro-3-[5-(3-fluoropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide impure of a dimeric by-product. This product was treated with a 9:1 TFA/water mixture (1 mL) and stirred at 60° C. for 1 h. The mixture was evaporated to dryness, taken up with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Hex/acetone 65:35) to give 24 mg of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=2/[CH:26]=[CH:27]\[CH3:28])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40].C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([O:23][C:35]3[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=3[F:29])=[O:22])=[CH:19][C:18]=2/[CH:26]=[CH:27]\[CH3:28])[CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(=O)O)ccc1N1CCN(CCOCc2ccccc2)CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: C/C=C\c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88.4 %

Procedure:
(Z)-4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-(prop-1-en-1-yl)benzoic acid (13 mg, 0.0331 mmol) was dissolved in ethyl acetate (3.3 mL). At room temperature, pentafluorophenol (7.3 mg, 0.0397 mmol) and N,N′-dicyclohexylcarbodiimide (8.2 mg, 0.0397 mmol) were added sequentially, and the mixture was stirred at room temperature for 14 hours. The reaction solution was added water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (16 mg (yield 86%)) was obtained as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[S:21][C:22]([CH:26]=O)=[C:23]([Cl:25])[N:24]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:26][C:22]2[S:21][C:20]([Cl:19])=[N:24][C:23]=2[Cl:25])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.5 %

Procedure:
To a solution of 4-(isobutylamino)-piperidine-1-carboxylic acid tert-butyl ester (797 mg, 2.28 mmol, 1 eq.) and 2,4-dichloro-5-thiazolecarboxaldehyde (500 mg, 2.75 mmol, 1.2 eq) in anhydrous dimethylformamide (10 ml), is added glacial acetic acid (130 uL, 2.28 mmol, 1 eq.) and NaBH(OAc)3 (677 mg, 3.19 mmol, 1.4 eq.). The reaction mixture is stirred at room temperature for 3 days and then water and ethyl acetate are added. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organics are washed with water, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue is purified on silica gel with 0 to 25% THF in hexanes to give 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-isobutyl-amino}-piperidine-1-carboxylic acid t-butyl ester (303 mg, 31%): m/z=422 (M+1); 1H NMR (250 MHz, CDCl3): δ=4.35 (2H, brd), 3.87 (2H, s), 2.80 (3H, m), 2.42 (2H,d), 1.86 (3H, m), 1.61 (11H, m), 1.06 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]([CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2ncnc(Cl)c21
Temperature: -78 °C
Yield: 56.8 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.4 g; 0.0023 mol; 1.0 equiv) in THF (15 mL) and cool to −78° C. under an argon atmosphere. Add drop-wise lithium hexamethyldisilazide (4.7 mL; 0.0047 mol; 2.0 equiv; 1 M in THF). Stir the reaction at −78° C. for 30 min. Add drop-wise methyl iodide (0.29 mL; 0.0047 mol; 2.0 equiv), allow the reaction temperature to come to −20° C. slowly and stir at −20° C. for 2 h. Quench the reaction with saturated ammonium chloride aqueous and extract with EA. Evaporate the organic layer to give the title compound (0.24 g; 41.38%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([O:18]C)=[O:17])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25].[OH-].[K+]>C1COCC1.CO>[CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([OH:18])=[O:17])=[CH:10][CH:11]=2)[N:6]([CH3:24])[C:5]1=[O:25]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-methylbenzoate (15-4) (550 mg, 1.5 mmol, 1.0 eq.) was dissolved in THF (2.5 mL)/MeOH (2.5 mL) and potassium hydroxide (340 mg, 6.0 mmol, 4.0 eq.) was added. The mixture stirred overnight at ambient temperature. Upon completion, the reaction mixture was concentrated and 1N HCl was added. The mixture was then extracted with ethyl acetate and the combined organics were dried over magnesium sulfate, filtered and concentrated to afford 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-methylbenzoic acid (55-1) as a white solid. MS (M+H)+: observed=354.0, calculated=354.2.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[Cl:20])[N:7]([CH2:21][CH2:22][CH2:23]O)[C:6]=2[C:5]([C:25]([O:27][CH3:28])=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([O:27][CH3:28])=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:13]([Cl:20])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=3[Cl:18])[CH2:23][CH2:22][CH2:21][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(Cl)cc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Yield: 87.4 %

Procedure:
To a mixture of methyl 4-chloro-1-(3-hydroxypropyl)-2-[(2,4,6-trichlorophenyl)amino]-1H-benzimidazole-7-carboxylate (250 mg, 0.540 mmol) and triethylamine (0.376 mL, 2.70 mmol) in tetrahydrofuran (2.7 mL) was added methanesulfonyl chloride (0.171 mL, 2.16 mmol) at 0° C. The resultant mixture was stirred at room temperature for 1 hr and concentrated in vacuo. After N,N-dimethylformamide (5.4 mL) and potassium carbonate (746 mg, 5.40 mmol) were added to the residue, the resultant mixture was stirred at 80° C. for 1 hr, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (210 mg, 0.472 mmol, 87%).
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:23]([O:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@H:13]3[O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=1.N(OC(C)(C)C)=O.N([O-])=O>C1COCC1>[C:15]([O:14][C@@H:13]1[C@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C@H:12]1[N:8]1[C:6]2[N:7]=[CH:2][NH:3][C:4](=[O:45])[C:5]=2[S:10][C:9]1=[O:11])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: CC(C)(C)ON=O
Agent: O=N[O-]
Solvent: C1CCOC1
Product: O=C(OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]cnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 6 (6.65 g, 10.6 mmol) in dry THF (350 mL) was added ter-butyl nitrite (6.2 mL, 52.3 mmol) and the mixture was stirred at room temperature for 1 h. Additional nitrite reagent (2.0 mL) was added and the mixture was stirred at 50°-60° C. overnight. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel using 8-10% acetone in CH2Cl2 followed by 10-11%. The desired product eluted last to yield 3.45 g (46%) of 9 as a foam: UV λmax (EtOH) 220 nm (ε 46600), 259 sh (11000), 271 sh (8400): 1H NMR (DMSO-d6) δ 6.31 (d, J=6.45 Hz, 1H, C1, H), 7.38-7.98 (m, 15H, benzoyl aromatics), 8.25 (s, 1H, C5H), 13.16 (b, 1H, N6H, exchanged with D2O), and other sugar protons.