Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[NH:37][C:38]4[CH:44]=[C:43]([C:45]([O-])=[O:46])[CH:42]=[CH:41][C:39]=4[N:40]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([NH:20][C:45]([C:43]4[CH:42]=[CH:41][C:39]5[N:40]=[C:36]([C:33]6[CH:34]=[CH:35][C:30]([N:27]7[CH2:26][CH2:25][O:24][CH2:29][CH2:28]7)=[CH:31][CH:32]=6)[NH:37][C:38]=5[CH:44]=4)=[O:46])=[CH:19][C:13]=3[N:12]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc2nc(-c3ccc(N(CCO)CCO)cc3)[nH]c2c1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2c1)c1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1

Procedure:
Compound 296 was prepared according to the procedure similar to that described in Scheme V from 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5-aminobenzimidazole and 2-(4-morpholinophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C35H35N7O4: 618.28; found: 618.03.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][OH:17].[H-].[Na+]>C1COCC1>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[N:11]3[CH2:15][CH2:14][CH2:13][C@@H:12]3[CH2:16][O:17][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@@H]2CO)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)OC[C@H]1CCCN21
Yield: 23 %

Procedure:
A suspension of (R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol (2.27 g, 9.4 mmol) and NaH (60% mineral oil suspension, 0.737 g, 18.9 mmol) in 35 mL THF was heated at reflux for 1 h. The reaction was quenched with phosphate buffer, and the aqueous layer was extracted with EtOAc. The solution was filtered through Celite, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Flash chromatography (3:2 EtOAc:hexanes) afforded 476 mg (22%) of (R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine, an orange solid. Data for (R)-2,3,3a,4-tetrahydro-7-nitro-1H-pyrrolo[2,1-c][1,4]benzoxazine: Rf 0.55 (3:2 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, 1H, J=9,2,2,4), 7.74 (d, 1H, J=2.4), 6.44 (d, 1H, J=8.8), 4.56 (dd, 1H, J=10.3, 3.4), 3.65-3.72 (m, 1H), 3.60 (broad t, 1H, J=8.6), 3.44 (t, 1H, J=10.0), 3.36 (td, 1H, J=9.8, 7.3), 2.15-2.25 (m, 2H), 2.05-2.15 (m, 1H), 1.45-1.55 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=O.[CH3:12][NH:13][CH3:14].[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:2]([N:13]([CH3:14])[CH3:12])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(C(C)=O)c1
Reactant: CNC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: COc1cccc(C(C)N(C)C)c1

Procedure:
Patent publication WO2004/037771 describes reductive amination of 3-methoxy acetophenone in presence of dimethylamine, titanium isopropoxide and sodium borohydride to obtain [1-(3-methoxyphenyl)ethyl]dimethylamine, which is further demethylated using hydrobromic acid to obtain 3-(1-dimethylamino)phenol. This is further resolved using (S)-(+)camphor-10-sulfonic acid and reacted with carbamoyl chloride to obtain rivastigmine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nn(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 179.6 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (5.02 g, 39.5 mmol) in DMF (80 mL) were added CH3I (10.01 mg, 70.52 mmol) and K2CO3 (9.97 g). The mixture was stirred at 60° C. for 2 h, quenched with water (100 mL), and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as brown oil (10.01 g, 89.79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[CH:14]([N:17]1[CH:21]=[C:20]([NH2:22])[CH:19]=[N:18]1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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].O1CCOCC1>[CH:14]([N:17]1[CH:21]=[C:20]([NH:22][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=2)[CH:19]=[N:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)n1cc(N)cn1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2cnn(C(C)C)c2)ncc1C(F)(F)F
Yield: 16.7 %

Procedure:
To a microwave tube was added 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (112 mg, 0.53 mmol), 1-isopropyl-1H-pyrazol-4-amine (55 mg, 0.44 mmol), cesium carbonate (0.287 g, 0.88 mmol), XPhos (21 mg, 0.044 mmol), Pd2(dba)3 (20 mg, 0.02 mmol) and dioxane (2.5 mL). The tube was sealed and the reaction was irradiated in the microwave at 140° C. for 30 minutes. The reaction mixture was then filtered and concentrated. The crude product was purified by reverse phase HPLC to give N2-(1-isopropyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (22 mg, 16%). LCMS (Method A): [MH+]=301.1 at 3.2 min. 1H-NMR (DMSO): δ 9.43 (m, 2H), 8.08 (s, 1H), 7.89 (s, 1H), 7.54 (s, 1H), 6.96 (m, 2H), 4.43 (m, 1H), 2.92 (d, J=8.0, 3H), 1.39 (d, J=6.6, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH3:18])([CH3:17])[C:12](=[O:16])[NH:13]2)=[CH:9][C:8]=1[N+:19]([O-])=O)=O.[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][C:4]1[NH:6][C:7]2[CH:15]=[C:14]3[NH:13][C:12](=[O:16])[C:11]([CH3:18])([CH3:17])[C:10]3=[CH:9][C:8]=2[N:19]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc2c(cc1[N+](=O)[O-])C(C)(C)C(=O)N2
Agent: [Pd]
Solvent: CCO
Product: COCc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 5, 1.6 g. (5.4 mmole) 6-methoxymethylcarbonylamino-5-nitro-3,3-dimethylindolin-2-one are dissolved in 160 ml. ethanol and hydrogenated in the presence of 0.8 g. 10% palladium on charcoal at normal pressure and ambient temperature. After 360 ml. of hydrogen have been taken up, the catalyst is filtered off with suction and the filtrate is evaporated to dryness in a vacuum. The residue is purified over a silica gel column (elution agent: dichloromethane/methanol 95:5 v/v). The appropriate fractions are evaporated to dryness and the residue is recrystallised from isopropanol. There are obtained 800 mg. (60% of theory) of the title compound; m.p. 203°-205° C.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:8])[NH:5][C:6]=1[CH3:7].[Cl:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([N:5]2[C:6]([CH3:7])=[C:2]([I:1])[N:3]=[C:4]2[CH3:8])[CH:13]=[CH:12][N:11]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Cc1nc(I)c(C)[nH]1
Product: Cc1nc(I)c(C)n1-c1ccnc(Cl)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=329.2, 331.1 (M+H+) was prepared in accordance with the general method of example 1b from 4-iodo-2,5-dimethyl-1H-imidazole (CAS: [631897-38-6]) and 2-chloro-4-fluoropyridine.
Reaction SMILES: [ClH:1].C(O[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:15])[CH3:14])[CH:8]=1)=[NH:6])C.C(=O)([O-])[O-].[NH4+:20].[NH4+]>C(O)C>[ClH:1].[C:13]([C:9]1[CH:8]=[C:7]([C:5](=[NH:6])[NH2:20])[CH:12]=[CH:11][CH:10]=1)(=[O:15])[CH3:14]
Reactant: CCOC(=N)c1cccc(C(C)=O)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CC(=O)c1cccc(C(=N)N)c1

Procedure:
A mixture of 14 g. (0.08 mole) of 3-acetylbenzenecarboximidic acid ethyl ester, hydrochloride of A. above and 14 g. (0.15 mole) of finely ground ammonium carbonate in 100 ml. of ethanol is heated at boiling temperature in an open flask for 3 hours. The solution is cooled and the first small amount of precipitate is collected and is discarded. The filtrate is further cooled to precipitate 6.7 g. of product with a melting point of 193° (dec.).
Reaction SMILES: [CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:9][C:10]1([CH3:26])[S:14][C:13]2[C:15]([CH2:24][OH:25])=[C:16]3[S:20][C:19]([CH3:22])([CH3:21])[S:18][C:17]3=[CH:23][C:12]=2[S:11]1.C([Li])CCC.CCCCCC.[CH3:38][Si:39]([CH3:42])([CH3:41])Cl>C(OCC)C>[CH2:1]([OH:8])[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:38][Si:39]([CH3:42])([CH3:41])[C:23]1[C:12]2[S:11][C:10]([CH3:26])([CH3:9])[S:14][C:13]=2[C:15]([CH2:24][OH:25])=[C:16]2[C:17]=1[S:18][C:19]([CH3:21])([CH3:22])[S:20]2
Reactant: CC1(C)Sc2cc3c(c(CO)c2S1)SC(C)(C)S3
Reactant: C[Si](C)(C)Cl
Agent: NC(CO)(CO)CO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)Sc2c(CO)c3c(c([Si](C)(C)C)c2S1)SC(C)(C)S3
Temperature: 0 °C
Reaction time: 3 h
Yield: 138.5 %

Procedure:
Compound 1d (0.15 g, 0.17 mmol) was dissolved in dry diethyl ether (5 mL) and tetrametyhlethylendiamine (0.26 mL, 1.69 mmol) was added under argon atmosphere. The mixture was cooled at 0° C., n-butyl lithium 2.5 M in hexane (0.68 mL, 1.69 mmol) was added drop wise over 10 min and the mixture was left to reach RT. After stirring for 3 h at RT, the resulting brown solution was added drop wise at 0° C. to a solution of trimethylchlorosilane (0.65 mL, 5.08 mmol) in diethyl ether (2 mL). The solution was stirred at RT for 4 h and the formation of a white solid was observed. The solid was filtered off, washed with diethyl ether and the organic solution was concentrated under vacuum. The crude product was purified by gravimetric chromatography on silica gel eluting with 15:1 hexanes-ethyl acetate to afford the title compound as an orange powder (0.12 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][C:13]([CH3:15])=[CH2:14])[CH:6]=1)[CH3:2]>C(O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[O:11][C:13]([CH3:15])([CH3:14])[CH2:12][C:7]=2[CH:6]=1)=[O:16])[CH3:2]
Reactant: C=C(C)Cc1cc(C(=O)OCC)ccc1O
Solvent: O=CO
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)O2
Temperature: 110 °C

Procedure:
A mixture of formic acid (12 mL) and 4-hydroxy-3-(2-methylprop-2-enyl)benzoic acid ethyl ester (4.8 g, 0.022 mol) is heated at 110° C. for 15 minutes. The reaction mixture is cooled to room temperature and formic acid is removed under reduced pressure. Demineralized water is added to the residue and the aqueous layer is extracted with dichloromethane (3×15 mL). Combined organic layers are washed with demineralized water (1×15 mL) followed by brine (1×15 mL) and dried over sodium sulphate. Removal of solvent gives a viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, n-hexane:ethyl acetate, 90:10) to give 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH:5]3[C:4]=2[CH:3]=1.[CH:27](O)=O.C=O.[OH-].[Na+]>O>[CH3:27][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:5]2[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][CH2:11][CH:6]12
Reactant: O=CO
Reactant: Cc1ccc2c(c1)C1CN(CCCC(=O)c3ccc(F)cc3)CCC1N2
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)C1CN(CCCC(=O)c3ccc(F)cc3)CCC1N2C

Procedure:
A mixture of 8-methyl-2-[γ-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (7.5 g), formic acid (2.7 g) and formalin (2.2 g) is refluxed for 3 hours. After cooling, to the reaction mixture is added water, and the mixture is made alkaline with aqueous sodium hydroxide and extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and concentrated. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (4.1 g), m.p. 140° - 145°C (recrystallized from aqueous ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:3]=1[O:23][CH2:24][CH3:25]>[Pt].CO.CC(=O)OCC>[Cl:1][C:2]1[C:3]([O:23][CH2:24][CH3:25])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCOc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Yield: 70.8 %

Procedure:
4-[6-chloro-5-ethoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine (0.2 g, 1 eq) was stirred under hydrogen balloon with platinum on carbon (10 percent, 0.11 g, 0.1 eq) in a mixture of MeOH and EA (1:1, 8 mL) at room temperature overnight. The reaction mixture was then filtered through Celite, the volatiles in the mixture was removed in vacuo, and the residue was purified by flash chromatography to give a white solid (0.13 g, 83%).
Reaction SMILES: [F:1][C:2]([F:19])([C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].S(Cl)(Cl)=O.[CH3:24]O>>[F:19][C:2]([F:1])([C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18][CH3:24])=[O:17])[NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=C(O)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F

Procedure:
0.8 g (2.6 mmol) of 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-carboxylic acid are dissolved in 15.0 ml of methanol and then slowly admixed dropwise with 0.58 ml (7.9 mmol) of thionyl chloride. The reaction solution is then heated under reflux for 16 hours. After cooling, the solvent is removed under reduced pressure on a rotary evaporator and the residue is taken up in ethyl acetate. The organic phase is carefully admixed with saturated sodium hydrogencarbonate solution. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. This gives 0.75 g of methyl 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (96%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:20].[CH3:21][C:22](C)(C)C([O-])([O-])[O-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[CH3:21][C:22]1[O:20][C:3]2[CH:4]=[CH:5][C:6]3[NH:7][C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9][S:10](=[O:13])(=[O:12])[C:11]=3[C:2]=2[N:1]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc(O)c2N)N1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc3oc(C)nc23)N1
Yield: 79 %

Procedure:
A solution of the product of Example 352E (56.3 mg, 0.188 mmol) in anhydrous N,N-dimethylformamide (2 mL) was treated with trimethylorthoacetate (0.098 mL, 0.752 mmol) and p-toluenesulfonic acid monohydrate (1Mg) at room temperature for 3 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with 4% methanol/dichloromethane to give the title compound as a white crystalline solid (48 mg, 79%). MS (ESI−) m/z 322 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, J=7.17 Hz, 3 H) 2.69 (s, 3 H) 3.71 (s, 2 H) 4.17 (q, J=7.11 Hz, 2 H) 7.27 (d, J=8.82 Hz, 1 H) 8.02 (d, J=8.82 Hz, 1 H) 12.33 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20]/[C:21](=[N:23]\[OH:24])/[CH3:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:24][N:23]=[C:21]([CH3:22])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C(=N/O)NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Yield: 78.9 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-N—((Z)-1-(hydroxyimino)ethyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (174 mg, 0.524 mmol) in DMF (2 mL) was heated at 80° C. for 2-3 hrs. The solvent was then concentrated in vacuum and the residue was purified by silica gel column chromatography (0 to 5% MeOH/DCM) to provide (2S,5R)-6-(benzyloxy)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (130 mg, 79%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:25]1([NH:24][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:20][CH2:19]2)=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Yield: 79.2 %

Procedure:
Triethylamine (10.04 mL, 7.28 g, 72 mmol) was added to stirred, cooled (0° C.) mixture of 1-t-butoxycarbonylpiperidine-4-carboxylic acid (6.87 g, 30 mmol), aniline (2.73 mL, 2.79 g, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (9.16 g, 36 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×50 mL), aqueous sodium hydrogen carbonate (saturated, 2×50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (40:60) to give the title compound as a colorless foam (7.23 g, 79%), δH (250 MHz, CDCl3) 7.51 (2H, d, J 7.6 Hz), 7.32 (2H, t, J 7.6 Hz), 7.26 (1H, br s), 7.11 (1H, t, J 7.6 Hz), 4.19 (2H, m), 2.78 (2H, m), 2.38 (1H, m), 1.90 (2H, m), 1.77 (2H, m), and 1.47 (9H, s). m/e (ES+) 305 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[C:9]([CH:11]([C:20]([O:22][CH3:23])=[O:21])[C:12]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34]C(=O)OC(C)(C)C)=[N:32][CH:33]=1>CN(C=O)C>[NH2:34][C:31]1[N:32]=[CH:33][C:28]([CH2:27][C:11]([C:9]2[N:8]=[CH:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:10]=2)([C:20]([O:22][CH3:23])=[O:21])[C:12]([O:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])=[CH:29][CH:30]=1
Reactant: COC(=O)C(C(=O)OC1CCCC1)c1cn(C2CCCC2)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(N)nc1)(C(=O)OC1CCCC1)c1cn(C2CCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentyl methyl 2-(1-cyclopentyl-1H-imidazol-4-yl)malonate (0.46 g; 1.44 mmol) was dissolved in absolute DMF (5 ml). At 0° C., sodium hydride (50%; 0.07 g; 1.44 mmol) was added. The mixture was stirred at RT for 1 h and then cooled again to 0° C. Then tert-butyl (5-bromomethylpyridin-2-yl)carbamate (0.41 g; 1.44 mmol) was added, and the mixture was stirred at RT for 2 h. While cooling in ice, the mixture was quenched with H2O and then extracted twice with EA. The organic phase was separated off and dried over Na2SO4, and the solvent was removed under reduced pressure. Purification of the crude product through a cartridge (50 g of silica gel) resulted in 0.31 g of cyclopentyl methyl 2-(6-aminopyridin-3-ylmethyl)-2-(1-cyclopentyl-1H-imidazol-4-yl)malonate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:23]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:30](=[O:31])[CH2:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1cccnc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2cccnc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 3′-amino-5-formyl-6-methoxy-N-(3-pyridin-3-ylpropanoyl)-biphenyl-3-sulfonamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:37][O:38][NH2:39].N1C=CC=CC=1>C(O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24](=[N:39][O:38][CH3:37])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 46.5 %

Procedure:
To a solution of tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.19 mmol) in anhydrous ethanol (2.0 mL) was added O-methylhydroxylamine hydrochloride (80 mg, 0.96 mmol) and pyridine (80 μL, 0.99 mmol). The resulting yellow solution was heated to 90° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was mixed with water (2.0 mL) and extracted into ethyl acetate (3×2.0 mL). The combined organic phases were washed with brine (2×4.0 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. The residue was purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 95:5 to 60:40) to give the desired product as a white solid (44 mg, 46% yield). 1H-NMR (500 MHz, CD3OD) δ 8.29 (1H, s), 7.35 (2H, d), 7.26-7.32 (5H, m), 7.16-7.21 (2H, m), 4.01 (3H, s), 3.02 (2H, t), 2.83 (2H, t), 2.36-2.52 (4H, m), 2.04-2.16 (1H, m), 2.01 (2H, p), 1.81-1.92 (1H, m), 1.15-1.50 (9H, br m). LCMS (Method A) RT=8.28 min, M+H+=498.10.