Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[C:12]([N:17]=O)[CH:11]=[N:10]1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([NH:14][CH2:15][CH3:16])=[C:12]([NH2:17])[CH:11]=[N:10]1
Reactant: CCNc1c(N=O)cnn1-c1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCNc1c(N)cnn1-c1ccc(F)cc1F

Procedure:
A solution of 1-(2,4-difluorophenyl)-N-ethyl-4-nitroso-1H-pyrazol-5-amine (1.21 g, 5 mmol) in 20 mL of MeOH was hydrogenated for 3 h with hydrogen gas in a balloon in the presence of palladium (200 mg of the 10% wt. on activated carbon). The reaction mixture was filtered through a pad of celite washing with MeOH. The solvent was removed on the rotovap affording 1-(2,4-difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine as a bright orange viscous oil. This material was used without purification. MS (ES+): 224.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][OH:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([CH2:16][O:17][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OCc3ccccc3)C[C@H]2NC(=O)OC(C)(C)C)cc1

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine (5.00 g, 14.3 mmol) was dissolved in pyridine (50 mL). p-Toluenesulfonyl chloride (4.08 g, 21.4 mmol) and 4-(N,N-dimethyl)aminopyridine (174 mg, 1.43 mmol) were added thereto at room temperature, and the resultant mixture was stirred under a nitrogen atmosphere for 24 hours. Under cooling, ethyl acetate (200 mL) and 1 mol/L hydrochloric acid (200 mL) were added thereto, followed by extraction with ethyl acetate (200 mL×2). The organic layer was washed sequentially by 1 mol/L hydrochloric acid (100 mL), saturated sodium hydrogencarbonate (100 mL), and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:1), to thereby yield the title compound as a colorless amorphous substance (6.27 g, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30]([CH3:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CCOC(C)=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].C(Cl)Cl.O>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([CH2:31][N:30]([CH3:47])[CH3:29])=[CH:33][CH:34]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a sealed tube were added 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.10 g, 0.226 mmol), N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.081 g, 0.271 mmol), and potassium phosphate (tribasic) (0.192 g, 0.902 mmol) followed by 1,4-Dioxane (2.0 mL) and water (0.5 mL). The suspension was stirred with degassing under N2 for 10 min, followed by addition of PdCl2(dppf)-CH2Cl2 adduct (0.018 g, 0.023 mmol). The reaction vessel was sealed and stirred with heating at 100° C. (heat block) for 2 h. The contents were allowed to stir with cooling to RT overnight. The mixture was diluted with EtOAc followed by addition of silica gel. The mixture was concentrated in vacuo and the obtained solid purified by silica gel chromatography (dry loaded, eluent: 8-95% gradient of chloroform (containing 10% 2M Ammonia in Methanol) and DCM. The collected product was concentrated from DCM/MTBE and then dried in vacuum oven for 16 h. The title compound was collected as an off-white solid (45 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.76 (m, 2H), 1.83-1.94 (m, 2H), 1.97-2.07 (m, 2H), 2.09-2.19 (m, 11H), 2.21 (s, 3H), 3.44 (s, 2H), 4.39 (d, J=4.80 Hz, 2H), 5.34 (quin, J=7.14 Hz, 1H), 5.88 (s, 1H), 7.41 (m, J=8.34 Hz, 2H), 7.81 (m, J=8.08 Hz, 2H), 7.87 (d, J=1.01 Hz, 1H), 8.12 (s, 1H), 8.36 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.53 (s, 1H); LC-MS (ES) m/z=498.3 [M+H]+
Reaction SMILES: Cl.[NH2:2][OH:3].[K].[CH3:5][C:6]1([CH3:35])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:34])([F:33])[C:28]([O:30]CC)=O)=[CH:23][CH:22]=3)=[O:19])[CH:9]=[CH:8][C:7]1=2.Cl>CO>[OH:3][NH:2][C:28]([C:27]([F:33])([F:34])[C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:10]2[CH:9]=[CH:8][C:7]3[C:6]([CH3:5])([CH3:35])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]=3[CH:11]=2)=[O:19])=[CH:26][CH:25]=1)=[O:30]
Reactant: CCOC(=O)C(F)(F)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [K]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(F)(F)C(=O)NO)cc3)ccc21
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
Hydroxylamine hydrochloride (2.34 g, 33.7 mmol) was dissolved in methanol (12 mL) at 45° C. for 10 min in a 50 mL round bottom flask. B) Potassium hydroxyde (2.81 g, 50.0 mmol) was dissolved in methanol (7 mL) at 45° C. for 10 min in 25 mL round bottom flask. The solution B) was added in A) at 45° C. This mixture was stirred at 45° C. for 10 min and cooled to RT. The mixture was filtered and 5 mL of the filtrate were added at RT via syringe to a solution of ethyl 2-(4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)phenyl)-2,2-difluoroacetate 23 (0.10 g, 0.23 mmol) in methanol (4 mL). This mixture was stirred for 16 h at RT. A solution of HCl 1M was added to about pH=5. The aqueous layer was extracted with ethyl acetate (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. N-(4-((Hydroxycarbamoyl)difluoromethyl)phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamide EHT 4996 was obtained (123 mg, 97% yield) as an orange solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][C:12]([NH:14][NH2:15])=[O:13].C[Al](C)C.[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35](OC)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>C1(C)C(C)=CC=CC=1>[CH3:20][C:21]1[CH:30]=[C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([NH:15][NH:14][C:12](=[O:13])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:36])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: NNC(=O)CN1CCc2ccccc2C1
Reactant: COC(=O)c1cccc(Nc2cc(C)nc3ccccc23)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1C
Product: Cc1cc(Nc2cccc(C(=O)NNC(=O)CN3CCc4ccccc4C3)c2)c2ccccc2n1
Yield: 63.2 %

Procedure:
To a solution of 91 (205 mg, 1.0 mmol) in xylene (5 mL) was added trimethyl aluminum (2 M solution in hexanes, 0.75 mL, 1.5 mmol). The mixture was stirred under nitrogen for 10 minutes before the addition of methyl 3-(2-methylquinolin-4-ylamino)benzoate (49) (150 mg, 0.5 mmol). The reaction was heated at reflux overnight, quenched with water (2 mL), basified to pH 9 (2 N NaOH), and extracted with 7:3 CH2Cl2/MeOH. The organic layer was dried (K2CO3) and concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO2, gradient elution) to give 92 as a pale yellow oil (147 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:17])N(OC)C)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:18][Mg]Cl>C1COCC1>[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:17])[CH3:18]
Reactant: COC(=O)c1cc(Br)cc(C(=O)N(C)OC)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(C(C)=O)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 48.6 %

Procedure:
The compound methyl 3-bromo-5-(methoxy(methyl)carbamoyl)benzoate (2.3 g, 7.6 mmol) was dissolved in dry THF (50 mL), solution was cooled to 0° C. and methylmagnesium chloride (3M in THF, 2.5 mL, 7.6 mmol)) was added dropwise. The reaction mixture was slowly allowed to come to room temperature and stirred further for 6 h. The reaction mixture was cooled to 0° C. and quenched with saturated NH4Cl solution. The product was extracted with EtOAc. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5% EtOAc in petroleum ether) to get methyl 3-acetyl-5-bromobenzoate (0.95 g, yield 49%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.51 (t, J=1.3 Hz, 1H), 8.37 (t, J=1.7 Hz, 1H), 8.28 (t, J=1.6 Hz, 1H), 3.97 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]([O:22][C:23](=[O:25])[CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:7][CH:6]=[CH:5][CH2:4]1)=[O:2].[Cl-].[NH4+]>O1CCCC1.[Mg]>[C:1]([O:2][CH:1]([C@H:3]1[C@@H:8](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH:13]([O:22][C:23](=[O:25])[CH3:24])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH2:10][CH2:11][CH2:12][CH2:13][OH:22])(=[O:2])[CH3:3]
Reactant: CCCCCCCCC(/C=C/C=C/[C@H]1CC=CC[C@H]1C=O)OC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCCCCC(/C=C/C=C/[C@H]1CC=CC[C@H]1C(CCCCO)OC(C)=O)OC(C)=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 146.2 %

Procedure:
A solution of 4.2 g of cis-(1RS)-1-formyl-(6RS)-6-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-3-cyclohexene in 8.25 ml of tetrahydrofuran is installed in 29.9 ml of this magnesium organic solution at -20° C. under argon and stirred for 30 minutes at -20° C. It is mixed with 150 ml of saturated ammonium chloride solution, extracted three times with ether, the organic phase is shaken out with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (8+2), 4.1 g of the alcohol is obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:4].C(N(CC)CC)C.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:32][C@@H:33]1[O:35][CH2:34]1)(=O)=O>CN(C=O)C>[CH2:19]([N:10]1[C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][CH2:32][C@H:33]3[CH2:34][O:35]3)=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:20]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCn1c2ccccc2c2cc(NC(=O)CN)ccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CNC[C@H]3CO3)ccc21

Procedure:
To a solution of 2-amino-N-(9-ethyl-9H-carbazol-3-yl)-acetamide (6.1 g, 23 mmol) and triethylamine (6.3 mL, 45 mmol) in DMF (50 mL) was added a solution of (R)-(−)-glycidyl nosylate (5.9 g, 23 mmol) in DMF (20 mL). The resultant solution was stirred two days under nitrogen to form (S)-N-(9-Ethyl-9H-carbazol-3-yl)-2-(oxiranylmethyl-amino)-acetamide, which was then directly treated with diethyl amine (23 mL, 227 mmol) and methanol (100 mL). The mixture was stirred an additional two days, and then concentrated under reduced pressure to remove the methanol. The concentrated reaction was diluted with ethyl acetate (1 L) and washed with saturated aqueous Na2CO3 (1 L), water (2×500 mL), and then brine (250 mL). The organic solution was then dried (Na2SO4), concentrated under reduced pressure, and flash chromatographed (10:3:1 to 7:3:1 hexanes/diethylamine/acetonitrile) to give the title compound (4.4 g, 49%) as a brown oil which was converted to the dihydrochloride salt (methanol, ethereal HCl). The salt was then re-pulped from refluxing 2:1 ether/methanol to afford the dihydrochloride salt of the title compound as a colorless solid (3.5 g, 33%). MS m/z @ 397 (M+1).
Reaction SMILES: [OH:1][C@@H:2](C(O)=O)[C@@H:3](O)C(O)=O.[NH2:11][C@H:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].[NH4+].[OH-]>O>[C:2]([NH:11][C@H:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:1])[CH3:3]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Temperature: 2.5 °C

Procedure:
A suspension of (R)-2-amino-N-benzyl-3-methoxypropanamide (2R,3R)-dihydroxysuccinate (358.34 g, 1.0 moL, 1.0 eq) in water (720 mL) was cooled to 0-5° C., and the pH adjusted to 10 to 10.5 by the addition of aqueous 28% NH4OH at below 10° C. The reaction mixture was extracted with dichloromethane (2×720 mL and 1×360 mL). The organic phase was charged with 4-(dimethylamino)pyridine (3.66 g, 0.03 moL), followed by acetic anhydride (112.3 g, 1.1 moL) slowly under constant stirring at 10-15° C. The reaction mixture was stirred at 10-15° C. for 30 to 60 min. The reaction mixture was heated to 20-25° C. and stirred for 1 hour. The reaction mixture was charged with water (1254 mL) and sodium bicarbonate (109.21 g, 1.3 moL) and stirred for 1 hour. The phases were allowed to separate and the aqueous phase was extracted with dichloromethane (2×360 mL) and concentrated to a volume of about 720 mL, charged with ethyl acetate (2.9 L) and concentrated to a volume of about 720 mL. This operation is repeated until the KF is less than 0.5%. The reaction mixture was charged with ethyl acetate (2.9 L) and heated to 60-65° C. Charcoal (3% by weight) was charged and the reaction mixture was heated to reflux and stirred for one hour. The reaction mixture was cooled to 60° C., filtered and the solid was washed with hot (60° C.) ethyl acetate (360 mL). The filtrate was cooled to 45-50° C. and stirred there for at least 4 hours and then cooled at 0-5° C. at a rate of 10° C./hour. The suspension was stirred for at least 3 hours to 0-5° C. and filtered. The resulting solid was washed with ethyl acetate (2×180 mL) and dried under vacuum at below 50° C. until a LOD of NMT 0.5% was obtained, to provide (R)-2-acetamido-N-benzyl-3-methoxypropanamide as a white solid (186.3 g, 75%, HPLC purity=99.8%, HPLC enantiomeric purity=100%).
Reaction SMILES: N1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.CCN(C(C)C)C(C)C.NC1CCN(CC[OH:51])CC1.[OH-].[Na+].C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.CCOCC>[OH:51][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:14][CH2:15]1
Reactant: NC1CCN(CCO)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8, 1 g, 4.29 mmol) is suspended in 5 ml of DMF, cooled to 0° C. and treated with Hünig's Base (1.46 ml, 8.58 mmol). The mixture is stirred for 15 min at 0° C. In a separate reaction flask, compound 192 (931 mg, 4.29 mmol) in 10 ml of DMF is cooled to 0° C., treated with 10M aqueous sodium hydroxide solution (0.858 ml, 8.58 mmol) and stirred for 15 min at this temperature. This solution is added to the above mentioned mixture, followed by benzotriazol-1-yl-oxytripyrrolidinphosphonium hexafluorophosphate (PyBOP, 2.34 g, 4.5 mmol) and stirred for 4 h at room temperature. The reaction mixture is diluted with ethyl acetate and washed with 2N sodium hydroxide solution, water and brine. Evaporation gave a semisolid, yellow crude product, which is treated with ether, filtered of and washed with ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S@:26]([CH:34]2[CH2:36][CH2:35]2)(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=1>>[CH2:32]([O:31][C:29]([N:28]=[S@:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)=[CH:25][CH:24]=1)([CH:34]1[CH2:35][CH2:36]1)=[O:27])=[O:30])[CH3:33]
Reactant: CCOC(=O)N=[S@](=O)(c1ccc(N)cc1)C1CC1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=[S@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Yield: 40 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)butan-1-ol (270 mg, 0.95 mmol) with (R)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (224 mg, 0.83 mmol) according to procedure 5c, the desired product is obtained in 40% yield (170 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: C(CCC(O)=S)(=O)C.S(Cl)(Cl)=O.[C:13]([S:16][CH2:17][CH2:18][C:19](Cl)=[O:20])(=[O:15])[CH3:14].Cl.[NH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[C:33]([OH:35])=[O:34].Cl>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:13]([S:16][CH2:17][CH2:18][C:19]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[C:33]([OH:35])=[O:34])=[O:20])(=[O:15])[CH3:14]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(O)C1CCc2ccccc2N1
Agent: CC(=O)CCC(O)=S
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)SCCC(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Acetylthiopropanoic acid (132 g) in toluene (200 ml) was treated with thionyl chloride (300 ml). The resulting solution was warmed on the steam bath for two hours, stirred overnight at room temperature then evaporated to dryness under reduced pressure, and finally distilled, to yield 139 g, b.p. (0.35-0.50 mm) 64°-66° of 3-acetylthiopropanoyl chloride. A solution of (±)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride (32.05 g) in pyridine (300 ml) was treated dropwise with 3-acetylthiopropanoyl chloride (25 g) with vigorous stirring. After stirring overnight, the reaction mixture was added to ice (600 g), acidified with concentrated hydrochloric acid, and extracted with ether. The combined ether extracts were concentrated under vacuum to a solid product, which was washed with cold ether (50 ml). This product, 1-(3-acetylthio-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, was crystallized from ethyl acetate-hexanes; yield 19 g, m.p. 89°-91°.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][C:32](O)=[O:33])=[CH:25][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C@@H:30]([NH:35][C:36](=[O:37])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:31][C:32]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([C:8]3[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=4[N:9]=3)[CH2:12]2)=[O:33])=[CH:25][CH:24]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2c(Cl)cccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2c(Cl)cccc21

Procedure:
(R)-4-chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (0.245 mmol, crude oil) (48A) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoic acid (0.319 mmol, 0.082 g) and N-methylmorpholine (1.47 mmol, 0.162 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.319 mmol, 0.121 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(4-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (48B) as a clear oil which was used without further quantification. ESI-ESI-MS: m/z 647.3 (M+H)+.
Reaction SMILES: COC1C=CC(O)=C(C2OC3C=CC=C(CNCC4C=CC=CN=4)C=3N=2)C=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][N:35]([CH2:43][C:44]1[C:49]2[N:50]=[C:51]([C:53]3[CH:58]=[CH:57][C:56]([O:59]COC)=[CH:55][CH:54]=3)[O:52][C:48]=2[CH:47]=[CH:46][CH:45]=1)[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:35]([CH2:43][C:44]1[C:49]2[N:50]=[C:51]([C:53]3[CH:54]=[CH:55][C:56]([OH:59])=[CH:57][CH:58]=3)[O:52][C:48]=2[CH:47]=[CH:46][CH:45]=1)[CH2:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=1
Reactant: COCOc1ccc(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)cc1
Agent: COc1ccc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)c1
Product: Oc1ccc(-c2nc3c(CN(Cc4ccccn4)Cc4ccccn4)cccc3o2)cc1

Procedure:
4-bis(2-pyridylmethyl)aminomethyl-2-(4-hydroxyphenyl)benzoxazole (F28) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F23) using 4-bis(2-pyridylmethyl)aminomethyl-2-(4-methoxymethoxyphenyl)benzoxazole (F21) (686 mg, 1.47 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F16) in 81% (500 mg); 1H-NMR (500 MHz, CDCl3) δ3.97 (s, 4H), 4.18 (s, 2H), 6.88 (d, 2H, J=9.0 Hz), 7.16 (dd, 2H, J=8.0, 4.5 Hz), 7.24 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.45 (d, 2H, J=8.0 Hz), 7.69 (t, 2H, J=8.0 Hz), 7.79 (d, 2H, J=8.0 Hz), 8.00 (d, 2H, J=9.0 Hz), 7.24 (d, 2H, J=4.5 Hz).
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:26][CH2:27][CH3:28])[C@@H:5]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][N:6]1C(=O)C1C=C(OC)C(O)=CC=1[N+]([O-])=O)[CH3:2].BrCCCBr.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.CCCCCC>CC(C)=O.O>[CH2:1]([O:3][CH:4]([S:26][CH2:27][CH3:28])[CH:5]1[CH2:9][C:8]([F:11])([F:10])[CH2:7][NH:6]1)[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CC(F)(F)CN1C(=O)c1cc(OC)c(O)cc1[N+](=O)[O-]
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(SCC)C1CC(F)(F)CN1

Procedure:
A solution of (2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)-4,4-difluoropyrrolidine 2-carboxaldehyde diethylthioacetal IV (1 mmol), 1,3-dibromopropane (0.5 mmol) and K2CO3 (3 mmol) in dry acetone (40 ml) was refluxed for 48 h. After the completion of reaction as indicated by TLC, EtOAc-hexane (6:4), the reaction mixture was poured on to the water and then extracted with ethyl acetate. Evaporation of the organic layer gave the crude product, which was further purified by column chromatography on silica gel eluting with EtOAc-hexane (1:1) to give the pure 1,1′-{[(Propane-1,3diyl)dioxy]bis[2-nitro-5-methoxy-1,4-phenylene)carbonyl]}bis[4,4-difluoropyrrolidine-2-carboxaldehyde diethylthioacetal] V.