Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:49])([F:48])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46]O)=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[F:48][C:14]([F:13])([F:49])[C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][CH:25]=[C:26]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][CH2:39][N:40]4[CH:44]=[CH:43][N:42]=[C:41]4[CH2:45][CH2:46][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])=[CH:32][CH:31]=3)[N:27]=2)=[CH:17][CH:16]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reaction time: 24 h
Yield: 172.1 %

Procedure:
Diethyl azodicarboxylate (1.86 ml) was added to a solution of 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (2.00 g), phthalimide (605 mg) and triphenylphosphine (1.08 g) in THF (30 ml) at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was diluted with ethyl acetate, successively washed with 1N aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 2-[2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]ethyl]-1H-isoindole-1,3(2H)-dione (4.31 g) as pale yellow crystals. 2-Aminoethannol (4.31 ml) was added to a solution of the product (3.94 g) in ethanol (70 ml), and the mixture was refluxed for 75 min. The reaction mixture was concentrated, diluted with ethyl acetate, successively washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex, 100-200 mesh, Fuji silicia chemical) (eluent; dichloromethane to dichloromethane:methanol=200:1 to 40:1) to give the titled compound (1.34 g) as a colorless amorphous form.
Reaction SMILES: [CH:1]1([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[CH3:15])=[CH:9][C:8]=2[C:28]([F:31])([F:30])[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.CCN(CC)CC.[BH3-]C#N.[Na+]>O1CCOCC1.O=[Mn]=O>[CH:1]1([C:7]2[CH:27]=[CH:26][C:10]([CH2:11][O:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:32]4[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]4)=[C:18]([CH2:24][CH3:25])[CH:17]=3)[CH3:15])=[CH:9][C:8]=2[C:28]([F:29])([F:30])[F:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CNC1
Reactant: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CO
Agent: O=[Mn]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCc1cc(C(C)=NOCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)ccc1CN1CC(C(=O)O)C1
Temperature: 50 °C

Procedure:
To a suspension of MnO2 (10 eq) in dioxane is added 1-(3-ethyl-4-hydroxymethyl-phenyl)-ethanone O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-oxime (1 eq). The resulting mixture is refluxed for 10 minutes. After filtration and concentration, the residue is dissolved in MeOH and treated with azetidine-3-carboxylic acid (2 eq) and Et3N (1.5 eq). The resulting mixture is heated at 50° C. for 30 minutes. After cooling to room temperature, NaBH3CN (3 eq) is added in portions. Purification by preparative LCMS results in 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid; 1H NMR (400 MHz, CD3OD) δ 1.24 (t, 3H), 1.30-1.60 (m, 5H), 1.74-1.92 (m, 5H), 2.28 (s, 3H), 2.79 (q, 2H), 2.92 (m, 1H), 3.68 (m, 1H), 4.32 (m, 4H), 4.51 (s, 2H) 5.22 (s, 2H), 7.38 (d, 1H), 7.50-7.68 (m, 5H). MS: (ES+): 517.3 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][CH3:21])=[C:13]([CH3:22])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([C:26]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:27]=1[O:28][CH2:29][CH2:30][NH2:31])([CH3:25])[CH3:24]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][CH3:21])=[C:13]([CH3:22])[C:10]=1[CH2:11][NH:31][CH2:30][CH2:29][O:28][C:27]1[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:26]=1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1c(C)c(C)c(OCc2ccccc2)c(C=O)c1C
Reactant: Cc1ccc(C(C)C)c(OCCN)c1
Solvent: c1ccccc1
Product: CCOc1c(C)c(C)c(OCc2ccccc2)c(CNCCOc2cc(C)ccc2C(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A solution of 2-benzyloxy-5-ethoxy-3,4,6-trimethylbenzaldehyde (2.98 g) and 2-(2-isopropyl-5-methylphenoxy)ethylamine (1.93 g) in benzene (50 ml) was refluxed under heating for 5 hours in a Dean-Stark extractor. The solvent was distilled off under reduced pressure and the residue was suspended in ethanol (100 ml). Sodium borohydride (0.40 g) was added with ice-cooling and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) to give 4.16 g of a colorless solid. The solid was recrystallized from methanol to give 1.62 g of the title compound (colorless needle crystals).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N+:4]([O-:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-])=O.O.Cl>Cl.[Fe].C(O)C>[NH2:8][C:7]1[CH:6]=[C:5]([CH3:11])[N+:4]([O-:12])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[n+]([O-])c(C)cc1N
Reaction time: 20 h

Procedure:
3,6-dimethyl-4-nitropyridazine-N-oxide (1.0 g), 0.5 mL water, 5 mL ethanol, 0.025 mL conc HCl and 1.0 g Fe powder were stirred together and heated under reflux. After 30 minutes an additional 1.0 g of Fe and 2 drops conc HCl was added to the mixture. After 2 hours an additional 1 g Fe and 2 drops of conc HCl were added and heating continued for another 5 hours, whereupon 5 mL EtoH, 1 g Fe and 2 drops conc HCl were added. Reflux was continued for 20 hours. The reaction was cooled filtered through celite, the celite washed with CH3OH and the filtrate was evaporated to give an orange oil which crystallized on standing (0.88 g yield). Used without further purification. ##STR27##
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[Si](C)(C)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C(Cl)Cl>[C:39]([NH:20][C:19]1[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:30])([F:31])[F:29])=[CH:22][N:15]([C@@H:13]2[O:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@@H:11]([OH:33])[CH2:12]2)[C:16](=[O:17])[N:18]=1)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(N)nc2=O)C[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
The starting material (8) (10 g, 20.43 mmol) was azeotroped in dry pyridine (2×100 ml) then dissolved in dry pyridine (160 ml) under N2 atmosphere. Chlorotrimethylsilane (10 ml, 79.07 mmol) added drop wise to the solution and stirred for 2 hours at room temperature. Benzoyl chloride (2.6 ml, 22.40 mmol) was then added to solution and stirred for one further hour. The reaction mixture was cooled to 0° C., distilled water (50 ml) added slowly to the solution and stirred for 30 minutes. Pyridine and water were evaporated from mixture under high vacuum to yield a brown gel that was portioned between 100 ml of sat. aq. NaHCO3 (100 ml) solution DCM. The organic phase was separated and the aqueous phase extracted with a further (2×100 ml) of DCM. The organic layers were combined, dried (MgSO4), filtered and the volatiles evaporated under reduced pressure. The resulting brown oil was purified by flash chromatography on silica gel (DCM:MeOH 99:1 to 95:5) to yield a light yellow crystalline solid (13) (8.92 g, 74%). 1H NMR (d6 DMSO): b 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.94 (m, 1H, H-2′), 2.27 (m, 1H, H-2′), 3.64 (d, 1H, J=11.6 Hz, H-5′), 3.75 (d, 1H, J=11.6 Hz, H-5′), 3.91 (m, 1H, H-4′), 4.09 (br m, 3H, CH2NH, H-3′), 5.24 (s, 1H, 3′-OH), 6.00 (m, 1H, H-1′), 7.39 (m, 2H, Ph), 7.52 (m, 2H, Ph), 7.86 (m, 1H, Ph), 8.0 (s, 1H, H-6), 9.79 (t, 1H, J=5.4 Hz, NHCH2), 12.67 (br s, 1H, NH). Mass (+ve electrospray) calcd for C27H33F3N4O6Si 594.67. Found 595.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:6])[CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C#N)c(F)c1

Procedure:
A solution of 1-bromobutane (18.0 g, 0.13 mol) in acetone (30 ml) was added dropwise to a stirred refluxing mixture of 2-fluoro-4-hydroxybenzonitrile (15.0 g, 0.11 mol) and potassium carbonate (46.0 g, 0.33 mol) in acetone (300 ml). The stirred mixture was heated under reflux for 21 h (glc analysis revealed absence of starting material). The product was extracted into ether (twice), and the combined ethereal extracts were washed with water, 5% sodium hydroxide, water and dried (MgSO4). The solvent and the excess of 1-bromobutane were removed in vacuo to yield a pale-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].Cl.[NH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:28]([O:29][CH3:30])=[N:27][N:26]([CH3:31])[C:25]1=[O:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[CH:12]=1)[O:5][CH2:6][C:7](=[N:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:28]([O:29][CH3:30])=[N:27][N:26]([CH3:31])[C:25]1=[O:32])[CH3:8]
Reactant: COc1nn(C)c(=O)n1-c1ccccc1CON
Reactant: CC(=O)COc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: COc1nn(C)c(=O)n1-c1ccccc1CON=C(C)COc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Yield: 20.7 %

Procedure:
To a stirred solution of the title compound of Step A (0.33 g, 1.5 mmol) in pyridine (30 mL) under a nitrogen atmosphere was added the title compound of Step C (0.43 g, 1.5 mmol) and the resulting mixture was heated at 90 ° C. for 2 h. The reaction mixture was allowed to cool to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 1 N aqueous HCl and was extracted three times with ethyl acetate. After drying (MgSO4), the combined organic extracts were concentrated under reduced pressure. Chromatography of the residue on silica gel (200 g) with 1:1 hexane: ethyl acetate afforded 0.14 g of the title compound of Step D, a compound of the invention, as an oil. 300 MHz 1H NMR CDCl3): δ 7.44 (m,3H), 7.23 (m,1H), 6.96 (m,1H), 6.81 (m,2H), 5.12 (q,2H), 4.44 (s,2H), 3.9 (s,3H), 3.43 (s,3H), 1.89 (s,3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].I[CH2:10][C:11]([OH:13])=[O:12]>CN(C=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:10][C:11]([OH:13])=[O:12])[CH3:2]
Reactant: O=C(O)CI
Reactant: CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
2-Ethoxyethanol (0.88 mL, 11 mmol) and sodium hydride (60% in oil, 1.08 g, 27 mmol) were stirred in DMF (20 mL) for 5 min. Iodoacetic acid (2.02 g, 10.9 mmol) was dissolved in DMF (20 mL) and added dropwise to the suspension. The thick orange suspension was stirred at rt for 3 hours. The reaction was quenched by slowly adding water (10 mL), followed by hydrochloric acid (4 M, 5 mL). The reaction mixture was extracted with dichloromethane (3×50 mL) and the combined organic layers dried over sodium sulfate, filtered and evaporated yielding a clear oil. The residue was purified by distillation under reduced pressure to give the product (1.1 g, 68%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9]C(=O)C(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[NH2:9][C:4]1[C:3]([CH2:1][OH:2])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncccc1CO
Yield: 53 %

Procedure:
A mixture solution of N-(3-formylpyridin-2-yl)-2,2-dimethylpropionamide described in Preparation Example J-2 (500 mg, 2.4 mmol) and an aqueous solution of 5N sodium hydroxide (7 mL) was refluxed for 90 minutes. After cooling, ethyl acetate and tetrahydrofuran were added for extraction, the organic layer was washed with brine, then, the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol:ethyl acetate=1:5), and the title compound (160 mg, 1.2 mmol, 53%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ccccc1

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (1.6 g) was treated with benzoyl chloride (1.1 eq.) and triethylamine (1.5 eq) in methylene chloride (50 mL). The reaction mixture was washed with 1 N HCl, sat, NaHCO3, and sat NaCl and the solvent removed to give product. LC-MS showed the product had the expected M+H+ of 279.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-:27])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cccc(Cl)c1-c1nc2c(F)cncc2s1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nc(-c3c(F)cccc3Cl)sc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To an ice-cooled solution of 2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.0 g, 14.16 mmol) in DCM (50 mL) was added m-CPBA (4.82 g, 0.028 mol) and the mixture was stirred at 5° C. for 1 hour. Additional m-CPBA (4.82 g, 28.0 mmol) was added and stirring at room temperature was continued for 18 hours. The suspension was diluted with DCM (50 mL) and washed with a potassium carbonate solution (100 mL). The aqueous phase was extracted with DCM (2×50 mL) and the combined organic layers were washed with water (100 mL), then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was triturated with diethyl ether (25 mL) to afford the title compound as a white solid (3.1 g, 73%). LCMS (Method E): RT=2.70 min, m/z: 299 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>O>[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:2]2[CH:3]=[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:23]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(Nc1cc(Cl)nn2ccnc12)c1ccccc1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(NS(=O)(=O)c3ccccc3)c3nccn3n2)CC1
Reaction time: 72 h

Procedure:
To N-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzenesulfonamide (100 mg, 0.325 mmol) from 1a was added trans-1,4-diaminocyclohexane (1000 mg, 8.77 mmol). The mixture was allowed to melt at 165° C. for 3 days. The melt was then cooled, water was added followed by extraction with dichloromethane. The organic layer was then concentrated in vacuo and purified by preparative HPLC. This gave 4.5 mg (2%) of the title compound as a TFA salt. 1H NMR (500 MHz, MeOH-D3) δ ppm 7.97 (2H, d, J=5 Hz), 7.85 (1H, s), 7.71 (1H, s), 7.63 (1H, m), 7.56 (2H, m), 6.63 (1H, s), 3.64 (1H, m), 3.12 (1H, m), 2.23-2.04 (4H, m), 1.51 (2H, m), 1.34 (2H, m). LC/MS m/e 387 (MH+). HPLC, 1.60 min. Waters Sunfire C18 4.6×50. 0%-100% B. B: 90% MeOH, 10% H2O, 0.1% TFA. A: 10% MeOH, 90% H2O, 0.1% TFA.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[H-].[Na+].Br[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[O:22])[CH2:15][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2)[CH3:21]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: CCOC(=O)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)CN1CCCCc2ccccc21

Procedure:
Add 2,3,4,5-tetrahydro-1H-benzo[b]azepine in small portions to a 0° C. suspension of 60% sodium hydride (3.0 g, 0.12 mol) in 300 mL of dimethylformamide. Upon complete addition of the amine, remove the ice bath and stir the reaction at 20-24° C. for 40 minutes. Add ethyl bromopyruvate (22.6 mL, 0.16 mol) and stir the resulting mixture at 20-24° C. for 6 hours. Add an additional 5 mL of ethyl bromopyruvate and stir the mixture for 1 hour. Quench by adding 50 mL of water then dilute with 1.5 L of dichloromethane. Separate the layers, wash the organic layer sequentially with water (2×500 mL) and saturated aqueous sodium chloride (500 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure at 60° C. Dissolve the residue in ethyl acetate (500 mL), wash sequentially with water (3×100 mL) and saturated aqueous sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5-10% EtOAc/hexanes to provide the desired compound as an off white solid (7.0 g, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH:11]([CH3:22])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH:11]([CH2:12][C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:14])[CH3:22])[C:29](=[O:32])[O:30][CH3:31])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: CC(CC(=O)c1ccc(F)cc1)N[C@@H](C)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(C(C)CC(=O)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
A solution of 3-((S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)butan-1-one (28.8 g, 79.2 mmol) and K2CO3 (100 g, 0.79 mol) in methylene chloride (1000 mL) was added methyl carbonochloridate (100 g, 0.72 mol) at 0° C. The formed mixture was stirred at rt overnight. The mixture was filtered and concentrated to give the crude product, which was purified by preparative HPLC to give methyl (S)-1-(4-bromophenyl)ethyl(4-(4-fluorophenyl)-4-oxobutan-2-yl)carbamate (7.5 g, 23%). 1H NMR (400 MHz, CDCl3): δ=1.28 (d, 3H), 1.52 (d, 3H), 2.59 (m, 1H), 3.72 (m, 5H), 5.43 (m, 1H), 6.98 (m, 3H), 7.16 (m, 2H), 7.31 (m, 2H), 7.60 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C[Si]([N:33]=[C:34]=[O:35])(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:33][C:34]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19])=[O:35]
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCNC(N)=O)c1ccccc1
Reaction time: 12 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in CH2Cl2 was added a large excess of trimethylsilyl isocyanate and triethylamine. After stirring for 12 h, the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 23-1 as a white solid. Data for 23-1: 1HNMR (500 MHz, d6-DMSO) δ 7.6 (m, 1H), 7.5-7.1 (m, 7H), 6.2 (s, 1H), 5.95 (m, 1H), 5.3 (s, 2H), 4.95 (m, 1H), 4.7 (m, 1H), 3.0 (m, 2H), 2.7 (s, 6H), 2.1 (m, 1H), 1.3 (m, 3H) ppm. HRMS (ES) calc'd M+H for C23H26ClFN4O2: 445.1801. Found: 445.1805.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]=[N+:16]=[N-:17])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8].[Cl:19][C:20](S(Cl)(=O)=O)=[CH2:21]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:21]=[C:20]([Cl:19])[N:17]=[N:16]3)[O:11][C:10]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C=C(Cl)S(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H](Cn2cc(Cl)nn2)CN1c1ccc(I)c(F)c1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
A stirred mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-azidomethyl-1,3-oxazolidin-2-one (1 g, 28 mmol) and 1-chloro-1-ethenesulfonyl chloride (1 g, 6.2 mmol) was heated in a pressure tube at 80° C. for one hour. The reaction mixture was cooled to room temperature, diluted with chloroform (15 mL), and heated at 80° C. for an additional 4 hours. The reaction mixture was cooled to room temperature and the precipitate was collected by filtration and washed with little dichloromethane to yield the title compound as a colorless amorphous solid (725 mg, 62%).
Reaction SMILES: [CH3:1][N:2]1[CH2:13][C:5]2[CH:6]=[CH:7][C:8]3[C:12]([C:4]=2[CH2:3]1)=[N:11][CH2:10][N:9]=3.C([O-])([O-])=O.[K+].[K+].[Br:20][C:21]1[CH:22]=[C:23](I)[CH:24]=[CH:25][CH:26]=1>CN1CCCC1=O.[Cu]>[Br:20][C:21]1[CH:26]=[C:25]([N:9]2[C:8]3[CH:7]=[CH:6][C:5]4[CH2:13][N:2]([CH3:1])[CH2:3][C:4]=4[C:12]=3[NH:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cccc(I)c1
Reactant: CN1Cc2ccc3c(c2C1)=NCN=3
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN1Cc2ccc3c(c2C1)NCN3c1cccc(Br)c1

Procedure:
A mixture of 6,8-dihydro-7-methyl-2H-pyrrolo[3,4-e]benzimidazole (0.25 g), K2CO3 (0.26 g), 3-bromo-1-iodobenzene (0.8 g) and Copper powder (15-20 mg) was heated in N-methyl-2-pyrrolidone (5 ml) at 180° C. for 3 hours. The mixture was then partitioned between EtOAc and water. The organic phase was dried over Na2SO4 and evaporated. The oily residue was purified on SiO2 with EtOAc as the eluent. 1H--NMR (500MHz,CDCl3) ppm: 2.8(s,3H), 4.2(s,2H), 4.45(s,2H), 7.2-7.7(m,6H aromatic) 8.1 (s, 1H imidazole).