Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C:19]([O:22][C:23]([N:25]1[CH2:31][C:30]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=2[O:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][O:13][C:11]([N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH2:27][CH2:26][N:25]([C:23]([O:22][C:19]([CH3:20])([CH3:18])[CH3:21])=[O:24])[CH2:31][C:30]=4[CH:32]=3)[CH:3]=2)[N:8]=[CH:9]1)=[O:12]
Reactant: CC(C)COC(=O)n1cnc2ncc(Br)cc21
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)CCO4)cc21
Temperature: 95 °C
Yield: 45.6 %

Procedure:
A flask was charged with isobutyl 6-bromo-1H-imidazo[4,5-b]pyridine-1-carboxylate (2.00 g, 6.82 mmol), (4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (2.00 g, 6.82 mmol), dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.14 g, 0.17 mmol), and diisopropylethylamine (3.50 g, 27.2 mmol) in dry dioxane (60 mL) and the mixture heated to 95° C. for 24 hours. The resulting mixture was diluted with ethyl acetate (100 mL) then washed with water (50 mL), 10% aqueous citric acid (50 mL) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, 1:1) to give 1,1-dimethylethyl 7-(1-{[(2-methylpropyl)oxy]carbonyl}-1H-imidazo[4,5-b]pyridine-6-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.45 g, 46% yield) as a brown oil. MS (EI) for C25H30N4O5: 467 (MH+).
Reaction SMILES: Cl[C:2]1[C:3]([C:15]([OH:17])=[O:16])=[N:4][N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:8])[CH:7]=1>CCO.[Pd]>[O:8]=[C:6]1[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[C:3]([C:15]([OH:17])=[O:16])[CH:2]=[CH:7]1
Reactant: O=C(O)c1nn(-c2ccccc2)c(=O)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(=O)n(-c2ccccc2)n1
Reaction time: 4 h

Procedure:
4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid (100 mg, 0.4 mmol) was dissolved in 3 ml EtOH and Pd/C (25 mg) was added. A H2 balloon was attached to the reaction vessel and the mixture was stirred for 4 h. The reaction was filtered through a pad of Celite®, concentrated and used without further purification in the next reaction. MS m/z: 217(100%, M+1)).
Reaction SMILES: Cl[C:2]([CH2:4][O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:3].[CH3:11][C:12]1(C)[O:17]C(=O)[CH2:15][C:14](=O)[O:13]1.N1C=CC=CC=1>ClCCl>[CH3:10][O:9][C:7]([CH2:6][O:5][CH2:4][C:2](=[O:3])[CH2:11][C:12]([O:13][CH2:14][CH3:15])=[O:17])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)COCC(=O)OC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
Methyl 2-(chloroformylmethoxy)acetate (216.6 g) was added over 45 minutes to a stirred solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (173.9 g) and pyridine (189.6 g) in dichloromethane (1000 ml) keeping the temperature below 5° C. The mixture was stirred at 5° C. for 30 minutes, allowing to warm up to room temperature over one hour, washed with 2.4M hydrochloric acid and water, dried over magnesium sulphate and evaporated. The resulting browm oil was dissolved in ethanol (300 ml) and the solution heated under reflux for 2.5 hours and evaporated. The residual oil was distilled to give the title compound (32.5 g), b.p. 138°-140°/l torr which was characterised by its N.m.r. spectrum in CDCl3, δ values: 4.27 (2H,s); 4.20 (2H, q, J 7 Hz); 4.16 (2H,s); 3.75 (3H, s); 3.54 (2H, s); 1.29 (3H, t, J 7 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:18]1([CH2:21][NH:22][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[CH2:20][CH2:19]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc2[nH]ncc2cc1NC1CCC(NCC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.4 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and cyclopropylmethylamine (54 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (13 mg) and a syn-form compound (7 mg).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9](C2C=CC=C(C(F)(F)F)C=2)=[CH:10][CH:11]=1)=[O:5].[O:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:33]=[CH:34][C:35]([CH3:41])=[C:36](B(O)O)[CH:37]=1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:36]2[CH:37]=[C:32]([C:28]3[O:27][CH:31]=[CH:30][N:29]=3)[CH:33]=[CH:34][C:35]=2[CH3:41])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(-c2ncco2)cc1B(O)O
Reactant: O=C(Nc1ccc(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Product: Cc1ccc(-c2ncco2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)s1

Procedure:
Compound 119 was synthesized in an analogous fashion as described for Compound 117 except that 5-(oxazol-2-yl)-2-methylbenzeneboronic acid was used instead of 3-trifluoromethylbenzeneboronic acid in the final step.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)=O.CC(C)=O.[H-].[Na+].[C:32](N1C=CN=C1)(N1C=CN=C1)=[S:33]>O1CCCC1>[S:33]=[C:32]1[N:12]2[C:13]3[N:14]([C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:4]=4)=[CH:10][CH2:11]2)[N:15]=[CH:16][C:17]=3[C:18](=[O:19])[NH:20]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a stirred solution of 1.00 g of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 4) in 30 ml of dry tetrahydrofuran cooled to -78° C. (dry ice-acetone) was added 286 mg of 60% sodium hydride (dispersion in mineral oil). The reaction mixture was stirred at -78° C. for 30 minutes then 637 mg of 1,1'-thiocarbonyldiimidazole was added. The mixture was allowed to slowly warm to room temperature and was stirred for 36 hours. The reaction mixture was quenched with water, neutralized with 5% aqueous hydrochloric acid and extracted with chloroform. Evaporation of the solvent in vacuo gave 934 mg of the desired product as a yellow solid, m.p. 251°-258° C. (dec).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH:17]C(OC)=O)=[CH:13][C:12]([F:22])=[CH:11][CH:10]=2)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:9]2[C:14]([C:15]=1[CH2:16][NH2:17])=[CH:13][C:12]([F:22])=[CH:11][CH:10]=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1c(CNC(=O)OC)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12
Agent: Cl
Product: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1cccc2ccc(F)cc12

Procedure:
salt with HCl (prepared according to Example 104.2.) was converted to 5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-3-(methoxycarbonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester as described in Example 77.1. which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 423.3 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](=[N:27]\[OH:28])/[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)Cc1ccccn1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(Cc1ccccn1)=N\O)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from (R)-4-(4-bromophenyl)-1-(pyridin-2-yl)-4-o-tolylbutan-2-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a colorless oil, MS (ESI+): m/z=409.0904 ([M+H]+, 1Br).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[I-].[Li+]>N1C=CC=CC=1>[Cl:23][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH:24]([CH3:26])[CH3:25])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1ccc(F)c(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1nc2ccc(Cl)cc2c(-c2ccc(F)c(Cl)c2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-quinoline-3-carboxylic acid methyl ester (60 mg, 0.15 mmol) and lithium iodide in pyridine. Off white solid (43 mg, 74%). LC-MS: 376 (M−H)−.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].ON1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH2:29])[CH3:25]>C(Cl)Cl>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH:29][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: CCOC(CN)OCC
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NCC(OCC)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl chloroformate (3 g, 0.027 mol.) and N-hydroxysuccinimide (3.8 g, 0.033 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added N,N-Diisopropylethylamine (7.0 mL, 0.04 mol). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 3 hrs at room temperature. DCM was evaporated and the residue was dissolved in 10 mL of acetonitrile, cooled in an ice-bath and then added dropwise a solution of aminoacetaldehyde diethyl acetal (4.7 mL, 1.2 eq). The resulting mixture was stirred at ice-bath temperature for 1 h and then overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was filtered, and the precipitate was washed with 2×10 mL DCM and dried over sodium sulfate. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give ethyl (2,2-diethoxyethyl)carbamate as a colorless oil
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:24]([O:27][CH2:28][CH2:29]Cl)[CH2:25]Cl>CN(C=O)C.O>[O:27]1[CH2:28][CH2:29][N:1]([C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(N2CCOCC2)c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a suspension of tert-butyl (3-aminophenyl)carbamate (7.59 g, 36.40 mmol), K2CO3 (10.06 g, 72.80 mmol) and NaI (16.37 g, 109.20 mmol) in DMF (300 mL) was added 2,2′-dichlorodiethyl ether (5.73 g, 40.1 mmol) slowly at 150° C. under N2. The reaction mixture was stirred at 150° C. overnight, then cooled to rt, poured into water (700 mL) and extracted with CH2Cl2 (200 mL×3). The combined organic phases were washed with water (200 mL×3) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as a yellow solid (5.91 g, 58%).
Reaction SMILES: [CH:1]([NH:3][C:4](=[C:9]1[CH2:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]1)[C:5]([O:7][CH3:8])=[O:6])=[O:2]>C(O)C.[C].[Pd]>[CH3:8][O:7][C:5](=[O:6])[CH:4]([CH:9]1[CH2:10][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12]1)[NH:3][CH:1]=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=C(NC=O)C(=O)OC)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC(C(NC=O)C(=O)OC)C1

Procedure:
A solution of methyl N-formyl-α-(3,3-diethoxycarbonylcyclobutylidene)glycinate (0.46 g, 1.47 mmol) in ethanol (40 ml) was hydrogenated over 10% palladium-carbon (100 mg) at 65 psi for 24 hours. The reaction mixture was filtered through a pad of celite and evaporated to give a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>ClCCl.O>[CH3:25][N:26]([CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([NH2:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4])[CH2:27][CH2:28][O:29][CH3:30]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COCCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and N-methyl-2-(methyloxy)ethanamine (1.4 g, 15.2 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT overnight. The reaction mixture was diluted with 100 mL of water, the organic solvents were washed with water (2×100 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was dissolved in 10 mL of EA, 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added, and the reaction was stirred at RT overnight under a balloon of H2 pressure. The catalyst was removed via filtration and the solvent was evaporated under reduced pressure to yield the 1-({methyl[2-(methyloxy)ethyl]amino}acetyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine as a white solid (3.1 g, 89%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 2.28(s, 3H), 2.62 (t, J=5.77 Hz, 2H), 2.94 (t, J=8.24 Hz 2 H), 3.19 (s, 3H), 3.25(s, 2H), 3.41 (t, J=5.77 Hz, 2 H), 3.68(s, 3H), 4.04 (t, J=8.33 Hz,2H), 4.61 (s, 2H), 6.67 (s, 1 H), 7.52 (s, 1 H).
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:67][C:68]1[O:69][C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=1>>[O:69]1[C:70]2[CH:76]=[CH:75][CH:74]=[CH:73][C:71]=2[N:72]=[C:68]1[S:67][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[N:40][C:41]([CH3:50])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCOCC2)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCOCC2)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(N2CCOCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(morpholino)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptobenzoxazole, to thereby yield the title compound as a colorless foamed substance.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([OH:29])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:30]([C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)=[O:33])[NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:31][NH:30][C:32]([N:34]1[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]1)=[O:33])=[O:29])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NN)CC1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
DIPEA (3.7 g, 10 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.45 g, 5.3 mmol, 0.8 eq.) and tert-butyl 4-(hydrazinecarbonyl)piperazine-1-carboxylate (1.6 g, 6.6 mmol) in dry DMF (50 mL), followed by the addition of HATU (1.45 g, 5.3 mmol). The reaction mixture was allowed to warm to rt then was stirred at rt overnight. The mixture was then diluted with water (200 mL) and the resulting precipitated material was collected by filtration, rinsed with water, and then recrystallized (3:1 petroleum ether/EtOAc) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperazine-1-carboxylate (1.4 g, 54%), ESI-MS (EI+, m/z): 503 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][C:14]2=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O>C(O)C>[C:24]1([C:22]2[N:1]=[C:2]3[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]4[C:17](=[O:18])[CH2:16][S:15][C:14]4=[O:19])=[CH:6][CH:5]=[CH:4][N:3]3[CH:21]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ncccc1OCCCCN1C(=O)CSC1=O
Solvent: CCO
Product: O=C1CSC(=O)N1CCCCOc1cccn2cc(-c3ccccc3)nc12

Procedure:
To a solution of 5.69 g (20 mmol) of 3-[4-(2-aminopyridin-3-yloxy)butyl]thiazolidine-2,4-dione in 40 ml of ethanol, 3.98 g (20 mmol) of bromoacetophenone was added at room temperature, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 5.24 g (68.7%, light orange crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:25])([CH:23]=[CH2:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[H-].[Na+].CI.Cl[CH2:31]Cl>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([O:25][CH3:31])([CH:23]=[CH2:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C=CC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: ClCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: C=CC(Cn1cncn1)(OC)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-[2-chloro-4-(4-chlorophenoxy)phenyl]-1-(1,2,4-triazol-1-yl)but-3-en-2-ol (0.4 g) was dissolved in THF (10 mL) and sodium hydride (0.03 g) was added. The mixture was stirred for 30 min at room temperature and methyl iodide (0.08 mL) was added. The mixture was then heated for 10 h to reflux. Brine and dichloro methane were added, the organic phase was dried and evaporated to obtain the crude product. This was purified by column chromatography to obtain 0.04 g of the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[NH:13]1[CH2:16][CH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1>C1(C)C=CC=CC=1>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([C:3](=[O:4])[CH2:2][N:13]2[CH2:14][CH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]2)=[CH:6][CH:7]=1)#[N:10]
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CN(CC(=O)c2ccc(C#N)cc2)C1
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a mixture of 4-(2-bromoacetyl)benzonitrile (448 mg, 2 mmol) in toluene (10 mL) was added tert-butyl azetidine-3-carboxylate (346 mg, 2.2 mmol). The reaction mixture was stirred overnight and then, solvent was removed. The solids were triturated with EtOAC. The solids were collected and dried in vacuo to yield 170 mg of tert-butyl 1-(2-(4-cyanophenyl)-2-oxoethyl)azetidine-3-carboxylate as an off white solid. MS (m+1)=301. HPLC Peak RT=0.97 minutes (Analytical Method B).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH2:22])[CH:10]=1.[C:29]([O:33][C:34](=[O:48])[CH2:35][CH2:36][S:37][CH2:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](O)=[O:43])([CH3:32])([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH:22][C:42]([C:41]2[CH:40]=[C:39]([CH:47]=[CH:46][CH:45]=2)[CH2:38][S:37][CH2:36][CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:48])=[O:43])[CH:10]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(F)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(F)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-fluoro-phenyl)isonicotinamide (200 mg, 0.51 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (200 mg, 0.68 mmol, 1.50 equiv), EDC.HCl (0.18 g, 0.94 mmol, 2.00 equiv), and 4-dimethylaminopyridine (58 mg, 0.48 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5˜ethyl acetate). The product was obtained as 100 mg (29%) of a yellow solid.