Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)([O-])=O.[H][H]>CO.[Pd].[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cccc([N+](=O)[O-])c2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCc2cccc(N)c2)CC1
Reaction time: 2.5 h
Yield: 63 %

Procedure:
A Parr glass liner was charged with tert-butyl 4-(3-nitrophenethyl)piper-azine-1-carboxylate (7C, 1.0 eq) and methanol (about 0.2 M 7C in MeOH). To this solution was added a slurry of 12.5 wt eq of 10% Pd/C in methanol. The reaction mixture was sealed in a Parr hydrogenation vessel and subjected to 3 pressurization/venting cycles with H2. The reaction mixture was allowed to proceed at room temperature and 45 psi H2 for 2.5 h. The reaction mixture was then charged with 12.5 wt eq of Pd(OH)2/C and the vessel was repressurized with hydrogen (45 psi). After 1 hr, the reaction mixture was filtered through a pad of diatomaceous earth, the diatomaceous earth washed with MeOH, and the combine organic layers concentrated in vacuo to provide the desired tert-butyl 4-(3-aminophenethyl)piperazine-1-carboxylate (7D, 63%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5](Br)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:12][CH:13]([OH:16])[CH:14]=[CH2:15].C1(N(C)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.CC#N>[NH2:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH2:15][CH2:14][C:13](=[O:16])[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(Cl)cc1Br
Reactant: C=CC(C)O
Agent: [Pd]
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CC#N
Product: CC(=O)CCc1cc(Cl)c(N)cc1C#N
Temperature: 90 °C
Yield: 60 %

Procedure:
5-amino-2-bromo-4-chlorobenzonitrile (1.1 g, 4.75 mmol), but-3-en-2-ol (0.445 g, 6.18 mmol), Pd2(dba)3 (0.044 g, 0.048 mmol), di-tert-butyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphine (0.045 g, 0.143 mmol), and N-cyclohexyl-N-methylcyclohexanamine (1.392 g, 7.13 mmol) were combined in a 20 dram vial and CH3CN (8 mL) was added. The vial was evacuated and backfilled with Ar 4×, and the reaction was heated at 90° C. for 45 min. The reaction was cooled to room temperature and diluted with water, extracting 3× with EtOAc. The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The material was then purified by flash column chromatography (0-70% EtOAc/Hex; 80 g column). 5-amino-4-chloro-2-(3-oxobutyl)benzonitrile (635 mg) was obtained as yellow foam.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][NH:15][CH2:16][C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18]>C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>[CH2:17]([O:19][C:20]([N:15]1[CH2:14][CH2:13][C:10]2[NH:11][C:12]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]=2[CH2:16]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1cccc2c3c([nH]c12)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2[nH]c3c([N+](=O)[O-])cccc3c2C1
Reaction time: 15 h
Yield: 55.9 %

Procedure:
6-Nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 0.99 mmol) was dissolved in CH2Cl2 (2.5 mL) with sat. aq. K2CO3. Ethylchloroformate (130 mg, 1.2 mmol) was added at 0° C. The reaction was brought to room temperature and stirred for 15 h. The layers were separated and the aqueous layer was extracted with CHCl3 (3×5 mL). The combined extracts were washed with brine (10 mL), dried (MgSO4) and evaporated affording ethyl-6-nitro-1,3,4,5-tetrhydro-2H-pyrido[4,3-b]indole-2-carboxylate as an orange semi-solid (160 mg, 56%). 1H NMR (CDCl3, 300 MHz) δ 8.17 (d, 1H, J=8.1 Hz), 7.78 (d, 1H, J=7.6 Hz), 3.19 (t, 1H, J=8.1 Hz), 4.73 (s, 2H), 4.18-4.23 (m, 4H), 2.91-2.98 (m, 2H), 1.30-1.39 (t, 3H, J=6.9 Hz) ppm.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=1[F:38])[NH:21][C:22]1[C:31]2[C:30]([OH:32])=[CH:29][C:28]([O:33][CH3:34])=[CH:27][C:26]=2[N:25]=[CH:24][N:23]=1.[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:49]([CH2:59]O)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:39]([O:46][C@H:47]1[CH2:51][N:50]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:49]([CH2:59][O:32][C:30]2[CH:29]=[C:28]([O:33][CH3:34])[CH:27]=[C:26]3[C:31]=2[C:22]([NH:21][C:20]2[CH:35]=[CH:36][C:37]([F:38])=[C:18]([Cl:17])[CH:19]=2)=[N:23][CH:24]=[N:25]3)[CH2:48]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: COc1cc(O)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
Di-tert-butylazodicarboxylate (DTAD, 692 mg) was added in one portion to a mixture of 4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-ol (640 mg), tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (830 mg), and triphenylphosphine (788 mg) in DCM (50 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 hours and then concentrated in vacuo to leave a brown oil. Purification by column chromatography, using 0-50% ethyl acetate in hexane as eluent, gave tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]-oxy}-2-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]-pyrrolidine-1-carboxylate as a white solid (884 mg, 70%); Mass spectrum MH+ 633.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.F[B-](F)(F)F.[O:22]=[N+:23]=[O:24].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:7]=1[N+:23]([O-:24])=[O:22]
Reactant: O=[N+]=O
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
276 mg (1.45 mmol) of ethyl 3-(4-chlorophenyl)-3-methylbutanoate were dissolved in 10 ml of dichloromethane, and the mixture was cooled to 0° C. A little at a time, 278 mg (1.38 mmol) of nitronium tetrafluoroborate were then added, and the mixture was stirred at a temperature between 0° C. and 10° C. for 4 h. 10 ml of water and 10 ml of dichloromethane were then added, and the phases were separated. The organic phase was dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 223 mg of the title compound (68% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O:10][K])=O)[CH2:3][C:4](=[O:7])[O:5][K].[CH3:12][O:13][C:14]([C@@H:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].Cl>>[NH2:1][C@H:2]([C:8]([NH:24][C@H:16]([C:14]([O:13][CH3:12])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])[CH2:3][C:4](=[O:7])[OH:5]
Reactant: N[C@@H](CC(=O)O[K])C(=O)O[K]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
80 μl buffer (0.5 M Hepes/Na+; pH 7) are added to 50 mg (0.2 mmol) AC-Asp(OK)-OK and 83 mg (0.4 mmol) H-Phe-OME.HCl in a closable polypropylene vessel and the components are immediately mixed intensively with a spatula. The reaction mixture is thermostatically controlled at 40° C. on a water-bath and the reaction is then started with 20 μl buffer comprising 4 mg thermolysin preparation (Sigma P 1512).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:30])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)N3CCCCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)N2CCCCC2)c1
Yield: 58.4 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(piperidine-1-carbonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (68 mg, 0.24 mmol) in methanol (6 mL) and 1N sodium hydroxide aqueous solution (2.5 mL, 2.5 mmol) was heated to reflux for 1 h. LC-MS showed the reaction was complete. The solvent was removed in vacuo to give white solid, which was dissolved in water and acidified with 1N hydrochloric acid solution to pH=2. The precipitated white solid was collected by filtration and back-dissolved in aqueous sodium hydroxide solution, then was acidified with 1 M hydrochloric acid solution again to pH=7. The white precipitated solid was collected by filtration and dried in vacuo to afford 55 mg of 3,3-dimethyl-2-(3-(piperidine-1-carbonyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. Yield: 83.8%. LC-MS(M+1)=393.2.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>C1C=CC=CC=1.O>[CH2:22]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.1 %

Procedure:
4.46 g (0.05 mole) of L-alanine was taken, and 13.3 g (0.055 mole) of cetyl alcohol was taken as an alcohol. After 200 ml of benzene was added thereto as a solvent, these materials were stirred and mixed. After the addition of 4.9 g (0.05 mole) of sulfuric acid as an acid catalyst, the resulting reaction mixture was heated under reflux. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with benzene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7 hours (at an internal temperature of 80.5° C.). After being cooled to room temperature, the reaction mixture was poured into a separating funnel and treated with 300 ml of a mixture of 0.2N NaOH and 6% NaCl solutions. This treatment was repeated three times. Thereafter, the benzene layer was isolated and washed thoroughly with water. After washing with water, the benzene layer was isolated and dried overnight over anhydrous sodium sulfate. Thereafter, the benzene layer was filtered and the resulting benzene solution was evaporated to remove the solvent. Thus, there was obtained 13.5 g (86.1% yield) of purified L-alanine cetyl ester in the form of an oily material.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[O-]S([O-])(=O)=O.[Ca+2].[F:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:23]1[C:27]2[NH:28][CH:29]=[N:30][C:31](=O)[C:26]=2[CH:25]=[N:24]1.CN(C)C=O>CC(C)=O>[Cl:3][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:23]([C:14]3[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:13]=3[F:12])[N:24]=[CH:25][C:26]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(=O)nc[nH]c32)c(F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Temperature: 130 °C
Yield: 89.7 %

Procedure:
POCl3 (379.1 g, 2.59 mol) was transferred under nitrogen to a 1 L round bottom flask fitted with a mechanical stirrer, a condenser and a tube connected above the condenser filled with a drying agent (drierite). 1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4) (100 g, 0.324 mol) was added to the reaction vessel, the contents were stirred, and a slurry was obtained. Dimethylformamide (DMF; 9.43 g, 0.129 mol) was added, and the reaction mixture was heated to reflux (oil bath set at 130° C.). After refluxing for 3 h, an additional amount of DMF (9.43 g, 0.129 mol) was added. The resulting mixture was refluxed for another 2 h and then gradually cooled to 55° C. Subsequently, acetone (270 mL) was added. The mixture was further cooled to 23° C. and a precipitate was obtained, which was isolated by filtration. The filtrate was quenched by slow dropwise addition into ice water (1.5 L) with stirring. During the quench, the internal temperature was kept at 0° C. or below by cooling with an ice-salt bath. Product 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) crystallized out of the quenched mixtures was isolated by filtration. The solids from both filtrations were combined and washed with water (2×500 mL), 10% aqueous NaHCO3 (2×500 mL), and water (2×500 mL) until the filtrate was neutral. The washed solids were vacuum dried overnight at room temperature and dissolved in methylene chloride (600 mL). The resulting mixture was filtered to remove any residual starting material (4). Hexane (200 mL) was added to the filtrate and methylene chloride was removed by rotary evaporation under reduced pressure. Product crystallized from the hexane solution and was filtered to obtain (7) (95 g; 90%). HPLC analysis, 99.26% (purity, by peak area); 1H NMR (Bruker 400 MHz, CDCl3) δ 8.88 (s, 1H, Ar—H), 8.46 (s, 1H, Ar—H), 7.96 (m, 3H, Ar—H), 3.14 (s, 3H, —SO2CH3); mass spec. (electrospray), m/z 327 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH:5][C:6]([C:8]1[N:13]=[C:12]([NH:14]CC2C=CC=CC=2)[C:11]2[NH:22][C:23](=[O:32])[N:24]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]=2[CH:9]=1)=O)[CH3:4]>C1(C)C=CC=CC=1>[NH2:14][C:12]1[C:11]2[NH:22][C:23](=[O:32])[N:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:10]=2[CH:9]=[C:8]([C:6]2[O:1][N:2]=[C:3]([CH3:4])[N:5]=2)[N:13]=1
Reactant: CC(=NO)NC(=O)c1cc2c([nH]c(=O)n2Cc2ccccc2)c(NCc2ccccc2)n1
Solvent: Cc1ccccc1
Product: Cc1noc(-c2cc3c([nH]c(=O)n3Cc3ccccc3)c(N)n2)n1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 1 %

Procedure:
1-Benzyl-4-benzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (1-hydroxyimino-ethyl)-amide was suspended in toluene and sealed in a microwave vial (Biotage, 0.5-2.0 ml). The vial was sealed and heated under microwave irradiation (Biotage Initiator 8) for 15 minutes at 150° C. Sample heated in microwave for a further 30 minutes at 150° C., and again for a further 30 minutes at 150° C. The mixture was evaporated then partitioned between EtOAc (10 ml) and water (5 ml). The aqueous was extracted twice more with EtOAc (2×10 ml) then the combined organics were dried (MgSO4) and evaporated. The residue was suspended in acetonitrile (2 ml) and this mixture was sealed in a microwave vial then heated under microwave irradiation for 30 minutes at 170° C., then at 190° C. for a further 30 minutes. The reaction mixture was concentrated in vacuo then dissolved in concentrated H2SO4 (2 ml). The solution was left to stir for 30 minutes then poured onto crushed ice. A saturated aqueous K2CO3 solution was added drop-wise until pH was ˜8. The aqueous was decanted from the solid into a separating funnel then extracted with EtOAc (3×15 ml). The combined organics were dried (MgSO4) and evaporated. The mixture of isomers was purified by HPLC on a Luna 10 micron C18(2) column (150×21.2 mmid). Eluted with 0.1% formic acid (aq) and 0.1% formic acid in MeCN at a flow rate of 25 ml/min. The gradient was isocratic at 5% organic for 0.6 minutes, then increased linearly from 5% to 90% organic over 8.50 minutes. The desired fractions were evaporated to give the title compound as a white solid (0.5 mg, 1%). LCMS Rt=2.46 m/z 323 [MH]+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:36][C@H:37]1[O:42][C@@H:41]([CH3:43])[CH2:40][N:39]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)[CH2:38]1.[OH-].[Na+]>COCCOC.C(Cl)Cl.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]>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:46]4[CH:47]=[CH:48][CH:49]=[C:44]([N:39]5[CH2:40][C@H:41]([CH3:43])[O:42][C@H:37]([CH3:36])[CH2:38]5)[CH:45]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: C[C@@H]1CN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)C[C@H](C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H]1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)C[C@H](C)O1
Temperature: 25 °C
Yield: 44.5 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), cis-2,6-dimethyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (58.5 mg, 0.153 mmol), Pd(dppf)2Cl2.DCM (8.32 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DME (2 mL) was heated at 80° C. for 10 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (CHCl3/EtOAc=2:1→1:1→1:2) to afford desired product (29.0 mg, 44.1%) as pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)COC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added iso-butyl chloroformate (121 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 15%-40%, 25 min) to give the title compound (185 mg, 38%) as TFA salt. 1H NMR DMSO 400 MHz δ 9.98 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.43 (q, 2H), 7.20 (d, J=8.8 Hz, 1H), 7.11 (q, 1H), 6.48 (s, 1H), 6.35 (q, 1H), 4.84 (s, 2H), 4.50 (s, 2H), 3.75 (d, J=7.2 Hz, 2H), 1.84 (q, 1H), 0.88 (q, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH3:37])[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][NH:16]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[N:13]([S:30]([O-:33])(=[O:32])=[O:31])[C:12]2=[O:34])=[O:9])[N:6]=1.[Na+].[H][H]>O.O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:35][O:36][CH3:37])[C:8]([NH:10][C@H:11]2[C@@H:14]([CH2:15][NH2:16])[N:13]([S:30]([OH:33])(=[O:31])=[O:32])[C:12]2=[O:34])=[O:9])[N:6]=1
Reactant: [H][H]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1CNC(=O)OCc1ccc([N+](=O)[O-])cc1)c1csc(N)n1
Agent: [Pd]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1CN)c1csc(N)n1

Procedure:
In a mixture of 15 ml of water and 15 ml of tetrahydrofuran is dissolved 203 mg of sodium cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(p-nitrobenzyloxycarbonylaminomethyl)-2-oxoazetidine-1-sulfonate (syn-isomer), followed by addition of 190 mg of 10% palladium-on-carbon. The mixture is stirred in a hydrogen atmosphere at room temperature for 3 hours. The catalyst is filtered off and the filtrate is washed with ethyl acetate and concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column and lyophilized to give a colorless powder. The powder is rechromatographed on a Sephadex LH-20 column and lyophilized to give cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-aminomethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([NH:16][C:17]([NH:19][CH2:20][C:21]#[CH:22])=[S:18])[CH:15]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH2:20][C:21]#[CH:22])[C:17]2=[S:18])[CH:15]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: C#CCNC(=S)Nc1cc(Cl)ccc1C
Solvent: ClCCl
Product: C#CCN1C(=O)C(=O)N(c2cc(Cl)ccc2C)C1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
Ethyl chlorooxoacetate (11.2 mL; 0.1 mol) was added dropwise while cooling in an ice bath to the stirring solution of N-(5-chloro-2-methylphenyl)-N′-(2-propynyl)thiourea (11.95 g; 0.05 mol) in methylene chloride (200 mL). The mixture was stirred for 18 hours at ambient temperature then evaporated to dryness. The residue was stirred in ether (200 mL) and the solids were collected by filtration and air dried to give 3.0 g 1-(5-chloro-2-methylphenyl)-3-(2-propynyl)-2-thioxo-4,5-imidazolidinedione, m.p. 162–164° C. Mass spectrum; (El, M.+) m/z 292/294. 1H-NMR (DMSO-d6; 300 MHz): δ 7.50–7.47 (m, 2H), 7.73 (d, 1H), 4.66 (q, 2H), 3.37 (t, 1H), and 2.15 ppm (s,3H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:28])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:10]([O:17][C:18]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:27][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:24][CH:25]=1)=[O:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(CO)cc1)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
Diisopropylethylamine (0.19 ml, 1.17 mmol) was added to a cool (0° C.) solution of (4-Hydroxymethyl-phenyl)-carbamic acid benzyl ester (0.25 g, 0.97 mmol) in DCM (8 ml) and the reaction stirred at this temperature for 5 minutes. After this time, methane sulfonyl chloride (0.09 ml, 1.07 mmol) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was then diluted with DCM (20 ml) and washed sequentially with saturated sodium bicarbonate solution (10 ml), saturated ammonium chloride (10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (0.29 g, 89% yield) as a yellow oil which was taken forward without further purification.