Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:30]([F:33])([F:32])[F:31])=[C:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)=[N:19][CH:20]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:35]([O:39][C:40](=[O:46])[C@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C.ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[C:35]([O:39][C:40]([C@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:30]([F:33])([F:32])[F:31])=[O:13])=[CH:20][N:19]=2)=[CH:22][CH:23]=1)=[O:46])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)cc1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)c1ccc(-c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoic acid (45 mg, 0.1 mmol), D-proline t-butyl ester hydrochloride (31 mg, 0.15 mmol), triethylamine (50 μL, 0.3 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (20 mg, 0.15 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.15 mmol) in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to give (R)-1-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-benzoyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (51 mg, 84%) as a white solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]([C@H:8]1[C:11](=[O:12])[NH:10][C@@H:9]1[CH2:13][C:14]([OH:16])=[O:15])([CH3:7])[CH3:6]>CCOCC.CO.C(O)(=O)C>[OH:4][C:5]([C@H:8]1[C:11](=[O:12])[NH:10][C@@H:9]1[CH2:13][C:14]([O:16][CH3:3])=[O:15])([CH3:7])[CH3:6]
Reactant: CC(C)(O)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C[C@H]1NC(=O)[C@@H]1C(C)(C)O
Temperature: 0 °C

Procedure:
A solution of diazomethane in ether (2 ml) was added to a solution of [(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (23 mg) in methanol (3 ml) at 0° C. and the mixture was stirred for an hour at 0° C. Acetic acid (2 drops) was added to the mixture at 0° C. and the mixture was evaporated in vacuo to give methyl [(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetate (25 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=C)[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:31])[C:14]=3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.33 h

Procedure:
OsO4 (6 mg, 0.023 mmol) was added to a stirred mixture of 1-[(4-methylphenyl)sulfonyl]-4-vinyl-1H-indole (68 mg, 0.23 mmol; Intermediate 4) and 2,6-lutidine (54 μL, 0.46 mmol) in dioxane (6 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.197 g, 0.92 mmol) in water (1.5 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 20 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and combined with Intermediate 5 batch 2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[BrH:13].O>CS(C)=O>[NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Br
Reactant: Cc1ccc(C(=O)O)c(N)c1C
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(Br)cc(C(=O)O)c(N)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-3,4-dimethylbenzoic acid (50.0 g) in DMSO (500 mL) was added hydrobromic acid (174 mL) while keeping the internal temperature at 25 to 30° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water (500 mL), and the mixture was stirred for 30 min. The precipitate was collected by filtration, and washed with water to give the title compound (102 g: containing DMSO).
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17](O)=[O:18])[N:6]2[N:5]=1)=[O:3].[CH3:24][NH:25][CH3:26].O1CCCC1.CN1CCOCC1.CN(C)C=O>>[CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=3[O:15][CH2:16][C:17]([N:25]([CH3:26])[CH3:24])=[O:18])[N:6]2[N:5]=1)=[O:3]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3OCC(=O)O)n2n1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN(C)C(=O)COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reaction time: 2.5 h
Yield: 76 %

Procedure:
[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetic acid (197 mg, 0.000594 mol), 2.0 M of Dimethylamine in Tetrahydrofuran (0.400 mL, 0.000800 mol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.147 g, 0.000767 mol) 1-Hydroxybenzotriazole (0.109 g, 0.000807 mol), 4-Methylmorpholine (0.0850 mL, 0.000773 mol) and N,N-Dimethylformamide (4.9 mL, 0.063 mol) were combined and stirred for 2.5 hours. The reaction was concentrated and purified by normal phase silica gel chromatography eluting with dichloromethane /methanol/ammonium hydroxide to yield a brown solid, 2-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-N,N-dimethyl-acetamide (162 mg, 76%). LCMS: m/z=359.13 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.89 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=4.7 Hz), 7.44 (m, 1H), 7.30 (d, 1H, J=4.7 Hz), 7.18 (d, 1H, J=8.4 Hz), 7.13 (m, 1H), 4.94 (s, 2H), 2.94 (s, 3H), 2.92 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [NH2:1][NH2:2].[OH-].[Na+].[CH2:5]([O:12][C@H:13]([C@H:16]([C@@H:25]([C@@H:34]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:35])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO.O1CCCC1>[NH:1]([C:14]([C@@H:13]([C@H:16]([C@@H:25]([C@@H:34]([CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[OH:35])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:15])[NH2:2]
Reactant: NN
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NNC(=O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1.77 g (55.5 mmoles) of anhydrous hydrazine (which has been twice distilled over NaOH) are dissolved in 3 ml of absolute methanol and the solution is cooled in an ice bath. While stirring 3.0 g (5.55 mmoles) of 2,3,4,6-tetra-O-benzyl-D-glucose dissolved in 15 ml of absolute tetra-hydrofuran were added dropwise. After a few minutes the ice bath is removed and the solution is heated to 50° C. At this temperature the mixture is stirred for 7 days in closed flasks. Following this the excess hydrazine is drawn off with the solvent at room temperature in a rotary evaporator. For removal of the last traces of hydrazine the substance is dried for 48 hours with an oil pump running. A colorless viscous sirup remained, yield: 3.05 g (100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH2:15][CH3:16])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNc1nc2ccccc2nc1Cl
Product: CCc1nnc2c(Cl)nc3ccccc3n12
Temperature: 25 °C
Yield: 85 %

Procedure:
2-Chloro-3-hydrazinoquinoxaline (4.5 g., 0.023 mole) the product of Example 1, was stirred with triethyl orthopropionate (50 ml.) at 100° C. for one hour. The mixture was cooled to room temperature and the white precipitate was collected by filtration and washed with cyclohexane to give 4.5 g. (85% yield) of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 158°-160° C. Mass spectrum: m/e, 232 (P).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:7]=1)[CH3:5].[C:18]([O-])([O-])=[O:19].[K+].[K+].[I-].[Na+].C[C:27]([CH3:29])=[O:28]>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:29][C:27]([O:19][CH3:18])=[O:28])[CH:12]=2)[CH:7]=1)[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: COC(=O)C(C)c1ccc2cc(O)ccc2c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)COc1ccc2cc(C(C)C(=O)OC)ccc2c1
Yield: 54.3 %

Procedure:
To a mixture of 2-(6-Hydroxy-naphthalen-2-yl)-propionic acid methyl ester 30 (175 grams, 761 mmol), anhydrous K2CO3 (315 grams, 2.279 mmol), sodium iodide (21 grams, 140 mmol) in anhydrous acetone (2000 mL) was added methyl Chloro acetate (104 grams, 958 mmol) and refluxed for 6 hours. Acetone was distilled and water (1500 mL) was added. Crude 31 was extracted into Ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using Benzene as eluant to give pure 31 (125 grams, 54.3%) as a pale yellow syrup. The structure was confirmed with NMR. IHNMR (CDCl3) δ 1.57 (d,3H,CH3), 3.64 (s,3H,Ester), 3.78 (s,3H,Ester), 3.80(q,1H,CH), 4.70(s,1H,Ar), 7.22(d,1H,Ar), 7.36(m,2H,Ar), 7.68(m,3H,Ar).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([O:16][C:17]2[C:18]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:13]([NH:29][C:30](=[O:32])[CH3:31])=[C:12]([F:33])[CH:11]=1.[ClH:34]>C(#N)C.[Cu]Cl.[Cu](Cl)Cl>[Cl:34][C:10]1[C:15]([O:16][C:17]2[C:18]([O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:13]([NH:29][C:30](=[O:32])[CH3:31])=[C:12]([F:33])[CH:11]=1
Reactant: Cl
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
A solution of 2.01 g of isoamyl nitrite in 1 ml of acetonitrile was added dropwise to a mixture of 2.0 g of N-[4-amino-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide, 1.13 g of copper (I) chloride, 2.31 g of copper (II) chloride, and 20 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]acetamide.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=O)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[C:1]([NH:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]#[N:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1nc(Cl)ccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)Nc1nc(Cl)ccc1C#N
Temperature: 55 °C
Yield: 80.6 %

Procedure:
To a solution of 2-tert-butylamino-6-chloro-nicotinamide (3, 850 mg, 3.73 mmol) in acetonitrile (anhydrous, 40 mL) were added pyridine (2.42 mL, 29.9 mmol) and POCl3 (1.37 mL, 14.9 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. The solution was extracted with EtOAc (3×50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification was accomplished by Biotage silica gel chromatography, eluting with 2%-30% EtOAc/hexanes gradient, to afford 630 mg (80% yield) of the title product.
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Cl:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Cc2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-benzylbenzyl alcohol (181.47 g) was dissolved into chloroform (100 ml), and thionyl chloride (66.8 ml) was added with stirring at a 0° C. After stirring at 0° C. for 4 hours, reaction mixture was concentrated under reduced pressure to give the title compound (198.34 g). This product was used in the subsequent procedure without purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25](=[S:27])[NH:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25](=[S:27])[NH:24][N:23]=2)[CH:8]=[C:9]([C:18]([CH3:19])([CH3:20])[CH3:21])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2n[nH]c(=S)s2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Yield: 48.7 %

Procedure:
Anhydrous zinc bromide (7.3 g, 0.033 mole) is added to a suspension of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,3,4-thiadiazole-2(3H)-thione (2.7 g, 0.007 mole) in methylene chloride (10 ml). After 18 hours the mixture is diluted with methylene chloride (50 ml), washed with water (20 ml), saturated aqueous NaHCO3 (20 ml), saturated aqueous NaCl (20 ml), and dried over MgSO4. Filtration and concentration gives a solid which is recrystallized from ethyl acetate/hexane to provide 1.1 g (2.1 g theor., 52%) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, mp 259.5°-260° C.
Reaction SMILES: C(O)=O.[CH2:4]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:18]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[CH2:4]([N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([NH2:18])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(CN2CCCCC(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Solvent: O=CO
Product: NC1CCCCN(Cc2ccccc2)C1
Yield: 72.8 %

Procedure:
Formic acid (0.25 ml, 6.63 mmol) was added dropwise to a solution of 1-benzyl-N-trityl-3-azepanamine (300 mg, 0.672 mmol) in methylene chloride (7 ml) under ice-cooling and stirred under ice-cooling for 3.5 hours. After the reaction mixture was concentrated, the residue was diluted with ether and washed with 1N-hydrochloric acid. After extraction, a 1N-aqueous sodium hydroxide solution was added to the aqueous layer under ice-cooling to make the aqueous layer basic, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate and then concentrated to obtain 1-benzyl-3-azepanamine (100 mg, 73%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[N:17][C:12]=1[N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)[CH2:7][CH2:8]1
Reactant: BrCCCCN1CCN(c2ncccn2)CC1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(CCCCn3cnc4ccccc43)CC2)nc1

Procedure:
A mixture of 6 g (20 mmol) of 2-[4-(4-bromobutyl)-1-piperazinyl]-pyrimidine, 2.36 g (20 mmol) of benzimidazole and 4.1 g (30 mmol) of potassium carbonate in 60 ml of dimethylformamide is refluxed for 14 hours. The reaction mixture is evaporated under vacuum, chloroform is added, the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 4.8 g of 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl}-1H-benzimidazole are obtained, which may be recrystallised from ethyl ether, with a melting point of 85°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][N:12]=3)[S:10][C:3]=12.[CH2:19](O)[CH2:20][OH:21].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[O:16]1[CH2:19][CH2:20][O:21][CH:15]1[C:14]1[CH:17]=[CH:18][C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:12][CH:13]=1
Reactant: OCCO
Reactant: O=Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(-c3ccc(C4OCCO4)cn3)sc12
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A suspension of 136 (2.69 g, 9.79 mmol), ethylene glycol (2.184 mL, 39.2 mmol), and (1R)-(−)-10-camphorsulfonic acid (0.227 g, 0.979 mmol) in toluene (150 mL) was heated to reflux with a Dean-Stark trap. After 3 h, the mixture was cooled down and filtered through celite (while still warm). The filtrate was washed with water, NaHCO3 (aq., sat.), NaOH (aq) and brine. The solution was then dried over MgSO4 and concentrated to afford compound 137 (2.77 g, 89% yield) as an off-white solid. MS (m/z): 319.1 (M+H).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:9][CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][OH:11]
Reactant: C[C@@H]1CCCN1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 24020.5 %

Procedure:
A mixture of (R)-2-methylpyrrolidine hydrochloride (4 g, 0.03 mol), 2-bromoethanol (3.7 g, 0.029 mmol) and K2CO3 (8.28 g, 0.0618 mol) in acetonitrile (50 mL) was stirred at room temperature overnight. The mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL). The combined filtrate was concentrated and the residue was purified on a silica gel column (MeOH/DCM=1/50) to give (R)-2-(2-methylpyrrolidin-1-yl)ethanol (0.9 g) as a colorless oil. 1H NMR (CDCl3): δ 3.63 (m, 2H), 3.14 (m, 1H), 2.95 (m, 1H), 2.44 (m, 1H), 2.24 (dt, 1H), 2.14 (m, 1H), 1.95 (m, 1H), 1.68 (m, 2H), 1.38 (m, 1H), 1.07 (d, 3H); LCMS: 130 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[Cl-:21]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1
Reactant: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Reactant: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine(19.18 g) was dissolved in chloroform (100 mL), and to the solution thinly chloride (10.2 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with aqaueous saturated sodium hydrogendcarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was then recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[CH:15]([NH2:27])[CH:16]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:17][C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:28])[CH:15]([NH:27][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:16]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:22][C:23]([F:25])([F:26])[F:24]
Reactant: COC(=O)C(N)C(CC(F)(F)F)CC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)cc1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.7 %

Procedure:
4-Chlorophenyl sulphonyl chloride (85 mg, 0.40 mmol) was added to a solution of 2-amino-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-pentanoic acid methyl ester (108 mg, 0.40 mmol) and pyridine (0.15 mL, 1.00 mmol) in CH2Cl2 (2 mL) and the reaction was subsequently stirred for 18 hours at 25° C. The solvent was removed in vacuo and the residue was dissolved in EtOAc (20 mL). This solution was washed with 1M HCl (2×10 mL) and brine (10 mL), dried over Na2SO4 and evaporated to afford a crude oil which was purified by flash chromatography, eluting with 20:80 EtOAc:hexanes, to provide the title compound (125 mg) as an oil in 70% yield. Mass Spectrum (−ESI): 446.0 [M−H]−.
Reaction SMILES: [OH:1][NH:2][C:3]([C@@H:5]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:43])[CH2:34][NH:35]C(OC(C)(C)C)=O)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:17])[CH2:6][NH:7]C(OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:35][CH2:34][C:33]([NH:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C@@H:5]([CH2:6][NH2:7])[C:3]([NH:2][OH:1])=[O:4])=[O:17])=[CH:19][CH:20]=2)=[CH:27][CH:28]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C#Cc2ccc(C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)NO)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)Nc1ccc(C#Cc2ccc(C(=O)N[C@@H](CN)C(=O)NO)cc2)cc1
Reaction time: 2 h
Yield: 104.4 %

Procedure:
To an oven-dried flask containing N-(4-{2-[4-(N-(1-(N-hydroxycarbamoyl)(1S)-2-[(tert-butoxy)carbonylamino]ethyl}carbamoyl)phenyl]ethynyl}phenyl)-2-[(tert-butoxy)carbonylamino]acetamide (6) (130 mg, 0.218 mmol) was added 1:1 TFA/CH2Cl2 (2.5 mL). The resulting pink solution was stirred for 2 h and concentrated to give a pink gum. The crude residue was rinsed with CH2Cl2 (4 mL), concentrated by rotary evaporation and dissolved in THF (2 mL) and MeOH (0.4 mL). A solution of 4 M HCl in dioxane (200 μL) was added and the resulting precipitate filtered and washed with Et2O (10 mL) to afford 90 mg of 4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-oxoethyl]benzamide as a pale tan powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH3:11][I:12]>>[IH:12].[CH3:11][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][C:2]1=[NH:10]
Reactant: CI
Reactant: Nc1nc2ccccc2s1
Product: Cn1c(=N)sc2ccccc21
Product: I
Yield: 62.2 %

Procedure:
Benzothiazol-2-ylamine (1.0 g, 6.6 mmol) and methyl iodide (0.48 mL, 7.9 mmol) were processed as described in Example 46A to provide 1.2 g (60%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 3.73 (s, 3H), 7.39-7.47 (m, 1H), 7.59 dt, J=7.8, 1.0 Hz, 1H), 7.65-7.71 (m, 1H), 7.99 (d, J=8.1 Hz, 1H), 9.99 (s, 2H); MS (DCI/NH3) m/z 165 (M+H)+.