Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:8]2.[Br:22][CH2:23][C:24](Br)=[O:25]>>[Br:22][CH2:23][C:24]([N:11]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1NNC1C2CC3CC(C2)CC1C3
Reactant: O=C(Br)CBr
Product: O=C(CBr)N(Nc1ccccc1[N+](=O)[O-])C1C2CC3CC(C2)CC1C3

Procedure:
1-(Adamantan-2-yl)-2-(2-nitrophenyl)hydrazine and bromoacetyl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and 1-(2-bromoacetyl)-1-(adamantan-2-yl)-2-(2-nitrophenyl)hydrazine was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[O:8][C:7](=[O:12])[NH:6][C:5]=2[S:4][CH:3]=1.[CH2:13](N1C2SC=CC=2C(=O)OC1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:6]1[C:5]2[S:4][CH:3]=[C:2]([CH3:1])[C:10]=2[C:9](=[O:11])[O:8][C:7]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1csc2[nH]c(=O)oc(=O)c12
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2sccc12
Product: Cc1csc2c1c(=O)oc(=O)n2Cc1ccccc1

Procedure:
This compound was prepared from 5-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (57) by applying the same method as described for the preparation of 1-benzyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione (58). Yield 4.2 g (56%); MP 183° C. 1H-NMR (DMSO-d6) δ 2.31 (s, 3H), 5.10 (s, 2H), 6.85 (s, 1H), 7.37 (m, 5H) ppm; EIMS m/z 274 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH2:16][CH2:17][CH2:18][C:3]1=2.[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+]>CO>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[C:16]1[C:4]2[O:5][C:6]3[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][C:7]=3[C:2](=[O:1])[C:3]=2[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3
Reactant: Cc1ccccc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCC3=Cc1ccccc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester, m.p. 156°-158° C. (5.1 g) was reacted with 2-methyl benzaldehyde (3.3 g) in methanol (80 ml) in the presence of sodium methylate (2.28 g) under stirring at room temperature for 20 hours. The precipitate was filtered and washed with methanol and then with water until neutral: crystallization from CH2Cl2 -methanol gave 5.2 g of 3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid, methyl ester, m.p. 203°-205° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[C:26]([CH3:42])=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:24]([CH3:23])[N:25]=[C:26]5[CH3:42])=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Cc1nn(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nn(C)c2ccc(-c3cc4ncn(C5CC5)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc12
Temperature: 105 °C

Procedure:
To a 25 ml 3-neck flask with condenser and magnetic stir bar was added (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (120 mg, 0.33 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (112 mg, 0.41 mmol) and Pd(PPh3)4 (32 mg, 0.027 mmol) then evacuated and filled with N2 3×. Added 2 mL DME and 2N SODIUM CARBONATE (0.41 ml, 0.82 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool. Workup: EtOAc, water, brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO, 24 g silica Gold, 0-6% MeOH/DCM to give desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[N:19]/[O:20][CH:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])/[C:14]([O:16]CC)=[O:15])[N:12]=1)=[O:6].[OH-].[Na+]>CO>[Cl:28][C:2]([Cl:1])([Cl:27])[CH2:3][O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[C:14]([OH:16])=[O:15])[N:12]=1)=[O:6]
Reactant: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1nc(C(=NOC2CCNC2=O)C(=O)O)cs1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.42 g of ethyl (Z)-2-[2-(2,2,2-trichloroethoxycarbonylamino)thiazol-4-yl]-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are suspended in 30 ml of methanol, and 3 ml of 2N sodium hydroxide are added thereto with ice-cooling. The mixture is stirred at room temperature for one hour and then refluxed for 30 minutes with heating. Then, the mixture is concentrated under reduced pressure to dryness. 5 ml of water are added to the residue, and the aqueous mixture is washed with ethyl acetate. The aqueous mixture is adjusted to pH 2 to 3 with diluted hydrochloric acid, and the mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran (2:1). The extract is dried and concentrated under reduced pressure to dryness. The residue is purified by silica gel chromatography (solvent, ethyl acetate:methanol=4:1). 0.4 g of (Z)-2-[(2-(2,2,2-trichloroethoxycarbonyl-amino)thiazol-4-yl]-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid is obtained. This product begins to gradually decompose at 190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3.S(OC)(O[CH3:24])(=O)=O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([O:19][CH3:24])=[O:18])=[CH:5][CH:4]=1)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCOCC1)O2
Reactant: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCOCC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.9 %

Procedure:
A suspension of the crude 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-carboxylic acid (2.17 g, 8.15 mmol), KHCO3 (2.58 g, 26.0 mmol) and dimethyl sulphate (1.58 mL, 16.7 mmol) in acetone (62 mL) was stirred at room temperature for two days before it was evaporated to dryness under reduced pressure. Ethyl acetate (100 mL) was added. The organic phase was washed with 0.5 M aqueous NaOH (6×30 mL) and evaporated to dryness under reduced pressure. The crude product was redissolved in dichloromethane (75 mL), dried over MgSO4 and evaporated to dryness under reduced pressure. Standard silica gel column chromatography afforded methyl 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-pyran]-4-carboxylate (1.87 g, 79%). 13C NMR (CDCl3) δ 164.9, 149.1, 147.2, 135.2, 124.0, 117.5, 107.1, 106.5, 65.2, 56.4, 51.8, 35.9.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:19][C:18](=[O:20])[N:17](CC3C=CC(OC)=CC=3OC)[S:16]2(=[O:33])=[O:32])=[CH:10][CH:9]=1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[OH:41][C:35]([C:37]([F:40])([F:39])[F:38])=[O:36].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[S:16](=[O:33])(=[O:32])[NH:17][C:18](=[O:20])[CH2:19]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2CC(=O)NS2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the title C compound, {4-[5-(2,4-dimethoxybenzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]phenyl}carbamic acid t-butyl ester (20 mg, 0.041 mmol) in CH2Cl2 (1 mL) is added TFA (1 mL). The reaction is stirred at RT overnight. Upon addition the reaction becomes light pink colored, progressing to deep purple after overnight. The solvent is evaporated and the residue is taken up in 2 mL of MeCN/water (50/50). This is filtered through a 0.2 micron PTFE membrane filter and the filtrate is collected. MeCN is removed under reduced pressure and water via lyophilization to give 5-(4-amino-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one TFA salt as a yellow foam: [M−1]−=240.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([S:19][CH3:20])[N:13]=[C:14](SC)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.Cl.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:14]1[C:15]2[N:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:9][C:10]=2[N:11]=[C:12]([S:19][CH3:20])[N:13]=1)[CH3:23]
Reactant: CSc1nc(SC)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: CCO
Agent: Cl
Product: CCOc1nc(SC)nc2sc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of Na (2.0 mg, 0.08 mmol) in ethanol (1 ml) was added 2-(4-fluorophenyl)-5,7-bis(methylthio)thiazolo[5,4-d]pyrimidine (50 mg, 0.15 mmol). The reaction mixture was heated at 80° C. for 3 hours. After cooling, the mixture was neutralized with 1N HCl and the solvent was removed under reduced pressure. The crude residue was redissolved in ethyl acetate, extracted with brine and dried over Na2SO4. After removing the solvents in vacuo, the residue was purified by flash chromatography on silica (EtOAc/Hex 1:50), yielding the title compound as a white solid (30 mg, 60%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=2[N+:27]([O-:29])=[O:28])[CH2:15][CH2:14]1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:23][C:22]1[CH:25]=[CH:26][C:19]([N:16]2[CH2:15][CH2:14][O:13][CH2:18][CH2:17]2)=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=1
Reactant: O=Cc1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: O=[N+]([O-])c1cc(C=NNC(=S)NC2CC3C=CC2C3)ccc1N1CCOCC1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (35 mg, 0.21 mmol) and 4-morpholino-3-nitrobenzaldehyde (68 mg, 0.287 mmol) similar to Example 3 and isolated as a yellow solid (42 mg, 52%). 1H NMR (CDCl3): 9.91 (s, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.22 (s, 1H), 7.58 (dd, J=8.8, 2.4 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.10 (ddd, J=8.1, 5.1, 2.7 Hz, 2H), 4.27 (t, J=8.7 Hz, 1H), 3.75-3.72 (m, 4H), 3.02-2.99 (m, 4H), 2.93 (s, 1H), 2.85 (s, 1H), 1.82 (ddd, J=7.6, 7.0, 2.4 Hz, 1H), 1.57 (m, 1H), 1.39-1.28 (m, 2H).
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.CO.[ClH:44].O1CCOCC1>>[ClH:44].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)c1cccc2ccccc12

Procedure:
A 237 mg portion of 6-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid was dissolved in 2.0 ml of 4 M hydrogen chloride/1,4-dioxane solution and 2.0 ml of methanol at room temperature and stirred for 62Hours. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) and then dissolved in 2.0 ml of ethyl acetate, mixed with 1.0 ml of 4 M hydrogen chloride/ethyl acetate solution and concentrated under a reduced pressure. The residue was dissolved in ethanol and mixed with ethyl acetate, and the thus obtained precipitate was collected by filtration and dried under a reduced pressure to obtain 40 mg of 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid hydrochloride as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=O.[O:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].N1CCCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=[C:30]1[O:26][C:27](=[O:32])[NH:28][C:29]1=[O:31]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OCc1coc(-c2ccccc2)n1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COc1cc(C=CC=C2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Reaction time: 72 h
Yield: 42.3 %

Procedure:
A mixture of 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (5.5 g), 2,4-oxazolidinedione (6.7 g), piperidine (1.4 g) and acetic acid (120 ml) was stirred for three days under reflux. The reaction mixture was cooled, and resulting crystalline precipitate was collected by filtration, which was washed with water, ethanol and isopropyl ether, successively to give 5-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamylidene]-2,4-oxazolidinedione (2.9 g, 43%), which was recrystallized from chloroform-methanol to afford yellow needles, m.p.227-228° C.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:11][CH:12]([OH:14])[CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)cn1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)cn1
Reaction time: 24 h
Yield: 69.4 %

Procedure:
A 500-mL Parr hydrogenation bottle was charged with 128a (1.9 g, 9.6 mmol), 10% palladium on carbon (50% wet, 570 mg dry weight) and ethanol (100 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 24 h on a Parr hydrogenation apparatus. The catalyst was removed by filtration through a pad of Celite 521 washing with 1:1 CH2Cl2:MeOH (500 mL). The resulting residue was purified by column chromatography eluting with a gradient of 100% DCM-100% 3:1 DCM:MeOH to afford a 70% yield (1.1 g) of 128b.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=O)[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CC(=O)CC1C
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A round bottom flask was charged with ethyl 2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180 mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were added dropwise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) was added portionwise and the reaction mixture was stirred at ambient temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (300 mL) and was stirred for about 20 min. The layers were separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na2SO4, and concd under reduced pressure. The crude yellow oil was purified via flash column chromatography eluting with a gradient of 0-30% EtOAc in heptane to give ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as a colorless oil: 1H NMR (pyridine-d5) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1>C(O)C.[Pd]>[C:13]1([C:4]2[N:1]=[C:36]([CH2:32][NH:1][C@H:4]3[C:13]4[C:8](=[C:9]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[CH:10]=[CH:11][CH:12]=4)[CH2:7][CH2:6][CH2:5]3)[O:35][C:34]=2[C:33]2[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (0.95 mg) and 10% Pd/C (0.2 g) in a mixture of ethanol (20 ml) and THF (20 ml) was stirred under H2 for 2 hours. The catalyst was filtered off and filtrate was evaporated. The residue was dissolved in DMF (10 ml) and then K2CO3 (600 mg) and (4,5-diphenyloxazol-2-yl)methyl bromide (700 mg) were added thereto. After being stirred for 2 hours at room temperature, the mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with water and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (1R)-1-(4,5-diphenyloxazol-2-yl)methylamino-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g).
Reaction SMILES: C([O:8][NH:9][C:10]([N:12]1[CH2:16][CH2:15][C:14](=[CH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([OH:26])=[C:20]([O:27][CH3:28])[CH:19]=2)[C:13]1=[O:29])=[O:11])C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[OH:8][NH:9][C:10]([N:12]1[CH2:16][CH2:15][C:14](=[CH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([OH:26])=[C:20]([O:27][CH3:28])[CH:19]=2)[C:13]1=[O:29])=[O:11]
Reactant: COc1cc(C=C2CCN(C(=O)NOCc3ccccc3)C2=O)cc(OC)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: COc1cc(C=C2CCN(C(=O)NO)C2=O)cc(OC)c1O
Yield: 62.8 %

Procedure:
To a solution of 800 mg (2 mmol) of 1-(N-benzyloxycarbamoyl)-3-(3,5-di-methoxy-4-hydroxybenzylidene)pyrrolidin-2-one in a mixture of anisole (12 ml) and nitromethane (12 ml) was added a solution of 1.6 g (12 mmol) of aluminium chloride in anisole (4 ml) under a nitrogen atmosphere while being stirred under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 6 ml of cooled 2N hydrochloric acid and the mixture was stirred for 1 hour and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was recrystallized from a methylene chloride/ether mixture to give 387 mg of the objective compound in 63% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[B-](F)(F)F.[O:17]=[N+:18]=[O:19].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:18]([O-:19])=[O:17])[C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]=O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
A solution of 4-chloro-2-nitrophenol (4 g, 23 mmol) in acetonitrile (100 ml) was cooled to −25 C.°, and gradually added with nitronium tetrafluoroborate powder (4.9 g). The reaction mixture was stirred for 2 hours while the temperature was raised to −10 C.°, and the reaction was stopped by adding 10 ml of water. The acetonitrile was evaporated under reduced pressure, and the residue was diluted with diethyl ether. The ether layer was washed with water, then washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated by vacuum concentration to obtain the title compound as yellow plate crystals (5.1 g).
Reaction SMILES: [CH:1]1([N:5]2[C:9]([C:10](=O)/[CH:11]=[CH:12]/N(C)C)=[CH:8][N:7]=[C:6]2[CH3:17])[CH2:4][CH2:3][CH2:2]1.[N:18]1([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[O:21]1[CH2:22][CH2:23][N:18]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]3[N:33]=[C:10]([C:9]4[N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[C:6]([CH3:17])=[N:7][CH:8]=4)[CH:11]=[CH:12][N:32]=3)=[CH:28][CH:29]=2)[CH2:19][CH2:20]1
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C1CCC1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)n1C1CCC1

Procedure:
The title compound was prepared from (2E)-1-(1-cyclobutyl-2-methyl-1H-imidazol-5-yl)-3-(dimethylamino)prop-2-en-1-one (Method 37 of WO 03/076435; 233 mg) and N-(4-morpholin-4-ylphenyl)guanidine (Method 4, 405 mg) by the procedure of Example 111 to yield a white solid (228 mg, 61%). NMR: 1.59-1.72 (m, 2H), 2.32-2.44 (m, 4H), 2.75 (s, 3H), 3.21-3.28 (m, 4H), 3.84-3.92 (m, 4H), 5.40 (quintet, 1H), 7.09 (d, 1H), 7.24-7.32 (m, 2H), 7.66 (d, 2H), 8.11 (s, 1H), 8.57 (d, 1H), 9.77 (brs, 1H); m/z 391.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=[C:18]3[N:17]([CH2:28][CH3:29])[C:16]2=[O:30])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[F:27][CH:25]([F:26])[O:24][C:22]1[CH:23]=[C:18]2[N:17]([CH2:28][CH3:29])[C:16](=[O:30])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(OC(F)F)cc21
Agent: [Pd]
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(OC(F)F)cc21
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-(difluoromethoxy)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (110 mg) and 10% palladium on carbon (40 mg) in MeOH (10 mL) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 6-(difluoromethoxy)-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (86 mg) as a pale yellow oil.