Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[N:15][C:14]([CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20])=[CH:13][N:12]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:22][O:21][CH:18]([O:19][CH3:20])[CH2:17][C:14]1[N:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: COC(Cc1cnc(NC(=O)OCc2ccccc2)cn1)OC
Agent: [Pd]
Solvent: CO
Product: COC(Cc1cnc(N)cn1)OC
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 5-(2,2-dimethoxy-ethyl)-pyrazin-2-yl-carbamic acid benzyl ester (130 mg, 0.4096 mmol) in methanol (5 mL) was treated with 10% palladium on activated carbon (30 mg). The reaction mixture was then hydrogenated under a hydrogen atmosphere at 25° C. and atmospheric pressure for 60 min, The mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford 5-(2,2-dimethoxy-ethyl)-pyrazin-2-ylamine (75 mg, 100%) as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH:8]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:7]3[C:6](=[O:15])[C:5]=2[CH:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][CH:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[CH:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH:8]3[CH2:9][C:10]=2[NH:1]1
Reactant: O=C1c2ccc(=O)[nH]c2CC2CCCCC12
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2

Procedure:
In close analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92) 6,7,8,9,9a,10-hexahydro-1H,5aH-benzo[g]quinoline-2,5-dione was treated with phosphoryl chloride (POCl3) to give after chromatographical separation the title compound as a colorless solid.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:13]=[C:12]([O:14][Si](C)(C)C)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1.Br[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29].O1CCOCC1.CO>CN(C=O)C>[F:33][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:12](=[O:14])[NH:13][C:4]2=[O:3])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: C[Si](C)(C)Oc1nc2c(c(O[Si](C)(C)C)n1)CCCC2
Reactant: COC(=O)c1cc(CBr)ccc1F
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)ccc1F

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 2. Reaction of the intermediate 2,4-di(trimethylsiloxy)-5,6,7,8-tetrahydroquinazoline with methyl 5-(bromomethyl)-2-fluorobenzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(4-fluoro-3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazol ine-2,4(1H,3H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(4-fluoro-3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-cyclopentylcarbonylpiperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(4-fluoro-3-(4-(cyclopentylcarbonyl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][O:21][CH3:22].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:20]([O:21][CH3:22])[CH3:19])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
4-Benzyloxybenzoic acid (5.0 g) and N,O-dimethyl-hydroxylamine hydrochloride (2.5 g) were suspended in dimethylformamide (50 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 g), 1-hydroxybenzotriazole (3.5 g) and triethylamine (3.6 ml) were added. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.6 g, yield 94%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:20])[OH:19])[CH2:12]3)=[C:5]2[NH:4][C:3]1=[O:21].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[C:24]([O:20][C:18](=[O:19])[NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:2]([CH3:1])[C:3](=[O:21])[N:4]([CH2:23][C:24]4[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=4)[C:5]=23)[CH2:12]1)([CH3:25])([CH3:31])[CH3:23]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cn1c(=O)[nH]c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Product: Cn1c(=O)n(Cc2cccc(C#N)c2)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccnc21
Yield: 105.2 %

Procedure:
The specific operation referred to the step (5) described in Example 1 for details. 347 mg (R)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl carbamic acid ter.-butyl ester (1 mmol) and 235 mg 3-(bromomethyl)benzonitrile (1.2 mmol) were charged. A column chromatography was performed to afford 292 mg titled product with a yield of 63.2%.
Reaction SMILES: Cl.[CH2:2]([O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[CH2:9][CH2:8]1)[CH3:3].[NH2:17][C@@H:18]([CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20]>>[CH2:38]([O:37][CH2:36][C@H:18]([NH:17][C:14](=[O:16])[CH2:13][N:10]1[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH2:2][CH3:3])[CH2:12][CH2:11]1)[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)=[O:20])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCOCCN1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOCCN1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 49.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-ethoxyethyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 242, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-ethoxyethyl)piperazin-1-yl)acetamido)propanamide (22.8 mg, 49.2%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.69 (m, 1H), 4.51 (s, 2H), 3.77 (m, 1H), 3.70 (m, 1H), 3.46-3.38 (m, 6H), 2.97 (s, 2H), 2.45 (t, 8H), 1.09 (t, 3H). MS (EI) for C32H39FN4O5. found 579.7 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Cl)cc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of 4-chlorophenol and 20 ml of dry dimethylformamide. is stirred at room temperature for 21 hours, then poured into 60 ml of water and extracted four times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained p-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 241°-242°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:14](=[O:23])[CH2:13][C:12]2=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:29](OC)[CH2:30][NH2:31]>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:12]3[NH:31][CH:30]=[CH:29][C:13]=3[C:14](=[O:23])[N:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:25][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Reactant: COC(CN)OC
Solvent: CO
Product: O=C1c2cc[nH]c2C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Temperature: 100 °C

Procedure:
To a solution of 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione (Intermediate 1A.4-1, 100 mg, 0.29 mmol) in methanol (0.1 ml) was added 2,2-dimethoxyethylamine (2 ml). The reaction was allowed to stir at 100° C. until the starting material was consumed. The reaction was concentrated in vacuo, and the residue was dissolved in toluene. The reaction was treated with a catalytic amount of p-toluenesulfonic acid and allowed to stir at 110° C. for 18 h. The crude reaction was purified via reverse phase chromatography to yield 1-benzyl-5′-(3-fluorophenyl)-1′H-spiro[piperidine-4,6′-pyrrolo[3,4-b]pyrrol]-4′(5′H)-one. LCMS (M+H) 376.1. 1H NMR (400 MHz, CD3OD) δ 7.50 (m, 7H), 7.23 (td, J=8.4, 2.1 Hz, 2H), 7.07 (m, 3H), 6.43 (d, J=2.8 Hz, 1H), 4.41 (s, 2H), 3.64 (d, J=13.6 Hz, 2H), 3.43 (t, J=12.6 Hz, 3H), 2.28 (td, J=14.1, 4.0 Hz, 2H), 2.02 (d, J=15.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([F:16])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.[Cl-].[Na+].O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]([F:16])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(OCc2ccccc2)CC1F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: OC1CCC(OCc2ccccc2)CC1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-(benzyloxy)-2-fluorocyclohexanone (3.8 g, 17.1 mmol) in methanol (60 mL) was added sodium borohydride (1.29 g, 34.2 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature, and left to stir for 45 min. The reaction mixture was treated with ammonium chloride solution and brine, and extracted with EtOAc. The combined organics were dried (magnesium sulfate), and concentrated to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:20]1[N:21]([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:23][CH:24]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:31]([C:26]2[C:25]([N:21]3[N:22]=[CH:23][CH:24]=[N:20]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:32])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-N-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 33; 100 mg, 0.32 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 66 mg, 0.35 mmol), EDC (91 mg, 0.47 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (65 mg, 0.47 mmol) and triethylamine (0.132 ml, 0.95 mmol) in DCM (1 ml) was stirred at room temperature overnight. The reaction was partitioned between water (5 ml) and DCM (5 ml), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[S:5][C:6]=1[CH:7]=O.[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=2[NH2:36])[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16].C([O-])(=O)C.[NH4+]>>[CH:15]([NH:18][C:19]([C@@H:21]1[C@H:26]([NH:27][C:28]2[C:33]([Cl:34])=[CH:32][N:31]=[C:30]3[N:35]=[C:7]([C:6]4[S:5][C:4]([N:9]5[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]5)=[N:3][C:2]=4[Cl:1])[NH:36][C:29]=23)[C@@H:25]2[CH2:37][C@H:22]1[CH:23]=[CH:24]2)=[O:20])([CH3:17])[CH3:16]
Reactant: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1sc(N2CCC(O)C2)nc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3nc(-c4sc(N5CC[C@@H](O)C5)nc4Cl)[nH]c23)[C@H]2C=C[C@@H]1C2
Yield: 7 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-(3-hydroxy-pyrrolidin-1-yl)-thiazole-5-carbaldehyde (180.77 mg, 0.77687 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid isopropylamide (208.72 mg, 0.62149 mmol), and Ammonium acetate (95.813 mg, 1.2430 mmol) were reacted to produce 23.87 mg (7%) of the title compound. (300 MHz, DMSO-d6) 12.60 (s, 1H), 8.10 (d, J=7 Hz, 1H), 7.92 (s, 1H), 6.38-6.31 (m, 2H), 5.16 (m, 1H), 5.02 (T, J=17 Hz, 9 Hz, 1H), 4.44 (s, 1H), 3.88 (m, 1H), 3.54 (m, 3H), 2.83 (s, 1H), 2.76 (s, 1H), 2.55 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 2.10 (m, 1H), 1.96 (m, 1H), 1.38 (d, J=8 Hz, 1H), 1.06 (d, J=7 Hz, 3H), 0.99 (d, J=7 Hz, 3H). MS=548 (M+H), HPLC: 2.52 min. (G Method)
Reaction SMILES: [NH2:1][C@H:2]([C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:33])[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:15]([S:24](C)(=O)=O)[N:16]3[CH:21]3[CH2:23][CH2:22]3)=[CH:11][C:10]=2[F:34])[CH2:5]1)[CH3:3].O.[SH-].[Na+]>COCCOC.O>[NH2:1][C@H:2]([C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:33])[C:14]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:15]([SH:24])[N:16]3[CH:21]3[CH2:22][CH2:23]3)=[CH:11][C:10]=2[F:34])[CH2:5]1)[CH3:3]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC)c(N3CC[C@@H]([C@H](C)N)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [SH-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(N3CC[C@@H]([C@H](C)N)C3)c(F)cc2c1=O

Procedure:
Compound 18 from previous reaction is partially dissolved in DME (150 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate (Aldrich, 72.6% by titration, 4.65 g, 60.2 mmol) in water (15.0 mL) is added to this solution. The resulting mixture is sparged slowly with argon for 30 min. The progress of the reaction is monitored by HPLC-MS, and judged to be complete (≦2% of 18 remains) after 15 h. Excess sodium hydrosulfide is quenched upon addition of aq HCl (30 mL, 6 N). The resulting orange solution (pH ˜2) is sparged with argon (3 h) to remove the generated hydrogen sulfide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(Br)c(C=O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To 2-bromo-5-methoxy-benzaldehyde (10 g, 31.25 mmol) in dichloromethane (30 ml) at −78° C. is added BBr3 (25 g, 93.75 mmol) and allowed to warm to room temperature. After 2 h, the reaction is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with water, brine, dried and purified by the column chromatography to afford 3.6 g of the titled compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH2:32][CH2:33][OH:34])[C:28]([NH:30][NH2:31])=[O:29])=[CH:23][CH:22]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39](/[CH:49]=[CH:50]/[C:51](O)=[O:52])[CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.C(Cl)CCl>[CH3:35][O:36][C:37]1[CH:38]=[C:39](/[CH:49]=[CH:50]/[C:51]([NH:31][NH:30][C:28](=[O:29])[CH:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:32][CH2:33][OH:34])=[O:52])[CH:40]=[CH:41][C:42]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1
Reactant: NNC(=O)C(CCO)c1ccc(F)cc1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: COc1cc(/C=C/C(=O)NNC(=O)C(CCO)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100.1 %

Procedure:
IPEA (0.17 mL), HOBT (134 mg) and EDC (190 mg) were added to a solution of 2-(4-fluorophenyl)-4-hydroxybutyric acid hydrazide (105 mg) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (153 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for 14 hours. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 224 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=1)([O-:24])=[O:23].CCN(C(C)C)C(C)C.[NH:43]1[CH2:48][CH2:47][NH:46][CH2:45][C:44]1=[O:49]>CN(C=O)C.O>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:46]2[CH2:47][CH2:48][NH:43][C:44](=[O:49])[CH2:45]2)=[O:31])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc([N+](=O)[O-])cc2)CCN1
Reaction time: 6 h

Procedure:
EDCI (0.394 gm, 2.05 mmol) and HOBT (0.276 gm, 2.05 mmol) were added to a stirred solution of the 4-nitrobenzoic acid (LX, 0.253 gm, 2.05 mmol) in anhydrous DMF. The temperature of the mixture was reduced to 0° C., at which time DIPEA (1.14 ml, 6.15 mmol) was added under nitrogen atmosphere and the resultant solution (or suspension) was stirred at room temperature for 30 min. 2-Piperazinone (LIX, 2.05 mmol) was then added at 0° C. The reaction mixture was then brought to room temperature and stirred for 6 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The organic layer was washed with water (3×10 ml), dried over anhydrous sodium sulfate, filtered and concentrated over the rotary evaporator to get the crude product. The crude product was purified by column chromatography (60-120 silica gel, ethyl acetate:hexane, 4:6) to afford pure product LXI (0.3 gm, 60%) as an off-white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:20])=[C:17]([Cl:30])[CH:16]=1.C(N(CC)CC)C>CCOC(C)=O>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:2](=[O:3])[O:4][CH2:5][Cl:6])[CH:29]=[CH:28][C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Reactant: O=C(Cl)OCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)OCCl)cc1Cl
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of chloromethyl chloroformate (4.27 mmol) in EtOAc (20 ml) was slowly added a solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (4.0 mmol) and triethylamine (4.45 mmol) in EtOAc (20 ml) under stirring. Stirring was continued at room temperature for 4 h. The reaction mixture was washed with water and 0.5 M tartaric acid, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography using Et2O/hexane 4:1 as eluent to give the title compound as white crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:21])=O>CN(C)C=O>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:21])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCCCCOc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 6-(4-nitrophenoxy)-hexanoic acid (20 g), thionyl chloride (40 ml) and dimethylformamide (0.5 ml) was refluxed for 5 hours. Excess thionyl chloride was distilled off under reduced pressure. Dry toluene (20 ml) added and solvent was removed under reduced pressure to obtain 6-(4-nitrophenoxy)-hexanoyl chloride (20 grams) as light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@:10]([NH:21][C:22](=O)OC(C)(C)C)([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.Cl[C:59]([O:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)=[O:60]>CS(C)=O>[F:68][C:65]1[CH:66]=[CH:67][C:62]([O:61][C:59](=[O:60])[N:21]([C@:10]2([CH3:20])[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH3:22])=[CH:63][CH:64]=1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.49 g (6.21 mmol) rac-tert-butyl (3R,4S)-1-benzyl-4-(4-chlorophenyl)-3-methylpyrrolidin-3-ylcarbamate, 0.836 g (7.45 mmol) potassium tert.-butoxide and 0.98 g (7.76 mmol) dimethyl sulfate in 80 mL DMSO was stirred at room temperature for 1 h. The mixture was poured onto ice-water and extracted with TBME. The combined organic layers were washed with brine, died with Na2SO4, filtered off and evaporated to dryness. The residue was dissolved in 40 mL DCM and 7.68 g (67.3 mmol) TFA was added. The mixture was stirred at room temperature over night and ice-water was added. The pH was adjusted to 12 and the organic layer was washed with brine. The aqueous layer was extracted with DCM and the combined organic layers were dried with Na2SO4, filtered off and evaporated to dryness. The residue was dissolved in 40 mL DCM and 1.04 g (8.08 mmol) DIPEA and at −15° C. 1.29 g (7.41 mmol) 4-fluorophenyl chloroformate was added. The mixture was stirred to 0° C. during 2 h and concentrated under vacuum the residue was purified by column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 1.68 g (59%) of the title compound as light brown viscous oil. MS m/e: 453.1 [M+H]+.