Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.[CH:24]1([NH:30][C:31]2[C:36]([C:37]([O:39]CC)=O)=[CH:35][N:34]=[C:33]([NH:42][C:43]([NH:45][CH2:46][CH3:47])=[O:44])[CH:32]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[CH:50]=1>CN(C=O)C.O>[CH:24]1([NH:30][C:31]2[C:36]([C:37]([NH:48][C:49]3[CH:50]=[C:51]([CH3:55])[CH:52]=[CH:53][CH:54]=3)=[O:39])=[CH:35][N:34]=[C:33]([NH:42][C:43]([NH:45][CH2:46][CH3:47])=[O:44])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1cccc(N)c1
Reactant: CCNC(=O)Nc1cc(NC2CCCCC2)c(C(=O)OCC)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(NC2CCCCC2)c(C(=O)Nc2cccc(C)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
EDCI.HCl (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 0.092 g, 0.480 mmol) and 1-hydroxybenzotriazole monohydrate (0.073 g, 0.480 mmol) were added to a stirred solution of ethyl 4-(cyclohexylamino)-6-(3-ethylureido)nicotinate iii (0.100 g, 0.320 mmol) in DMF (3 mL) at room temperature. After 15 min, m-toluidine (0.052 g, 0.480 mmol) was added and the reaction mixture stirred at room temperature for 24 h. The mixture was treated with water (5 mL) and the resulting colourless precipitate filtered, washed with water, air-dried and recrystallized from EtOH to afford Compound 3 (0.030 g, 0.076 mmol, 29%) as colourless microcrystals. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (1H, s), 9.01 (1H, s), 8.44 (1H, s), 8.28 (1H, br), 8.10 (1H, d, J 9.0), 7.52 (1H, s), 7.42 (1H, d, J 9.0), 7.20 (1H, t, J 6.0), 6.90 (1H, d, J 6.0), 6.66 (1H, s), 3.25-3.13 (3H, m), 2.29 (3H, s), 1.94-1.91 (2H, m), 1.67-1.57 (3H, m), 1.42-1.23 (5H, m), 1.08 (3H, t, J 7.2); [M+H]+ m/z=396.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]2)[CH2:3][CH2:2]1.O=[C:24]1[CH2:30][CH:29]2[N:31]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH:26]([CH2:27][CH2:28]2)[CH2:25]1.[BH4-].[Na+].ClC(OCC)=O.Cl>ClCCCl.COCCOC.CO.CC#N.CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.C(N(CC)CC)C>[CH2:35]([O:34][C:32]([N:31]1[CH:29]2[CH2:28][CH2:27][CH:26]1[CH2:25][CH:24]([N:1]1[CH2:2][CH2:3][C:4]3([C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]3)[CH2:5][CH2:6]1)[CH2:30]2)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCNCC2)C1
Reactant: O=C1CC2CCC(C1)N2C(=O)OCc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
tert-Butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4a (2.80 g, 8.263 mmol) and benzyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (2.014 g, 7.767 mmol) were dissolved in a mixture of DCE (10 mL) and DME (10 mL) and placed under a nitrogen atmosphere. Triethylamine (1.149 mL, 834.5 mg, 8.263 mmol) was added, followed by Ti(OiPr)4 (7.2 mL, 6.9 g, 24.6 mmol) and the reaction was allowed to stir at room temperature for 60 h. The reaction mixture was diluted with 30 mL MeOH and cooled to −40° C. to −50° C. NaBH4 (1.223 g, 33.051 mmol, 4.0 eq) was added portion-wise over 30 min and the reaction was allowed to stir at −40° C. until bubbling had subsided (approximately 3 h), was allowed to warm slowly back to room temperature and was stirred for 2 h. The sticky suspension was filtered through a pad of Celite, and the filter cake was washed with MeOH (2×30 mL) and Et2O (3×50 mL). The filtrate was separated into the corresponding layers, and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide the crude product as a white foam. Unreacted starting material was converted to the corresponding ethyl carbamates by suspending the crude product in CH3CN (30 mL) and treating sequentially with ethyl chloroformate (1 mL) and triethylamine (2 mL). After 10 min, the mixture was diluted with Et2O (300 mL) and poured onto 1N aq HCl (300 mL). The biphasic suspension was filtered, and the precipitate was washed with HCl 1N (2×30 mL), H2O (2×30 mL) and Et2O (3×30 mL) and dried to provide tert-butyl 1′-(8-(benzyloxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate 4b as the hydrochloride salt (2.7 g, 56% yield). LC/MS m/z [M+H]+ 546.4, retention time 2.92 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [CH2:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)[CH2:2][CH3:3].Br[CH2:14][C:15]1[CH:35]=[CH:34][C:18]2/[C:19](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:20]3[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:21]=3[O:22][CH2:23][C:17]=2[CH:16]=1>>[F:28][C:26]1[C:25]([F:29])=[CH:24][C:21]2[O:22][CH2:23][C:17]3[CH:16]=[C:15]([CH2:14][N:8]4[C:7]5[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=5[N:5]=[C:4]4[CH2:1][CH2:2][CH3:3])[CH:35]=[CH:34][C:18]=3/[C:19](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:20]=2[CH:27]=1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)c(F)cc21
Reactant: CCCc1nc2ccccc2[nH]1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)COc1cc(F)c(F)cc1/C2=C(\C)C#N
Yield: 90.6 %

Procedure:
Using 2-propyl-1H-benzo[d]imidazole (Synthetic Communication, 2002, vol. 32, p 3703; 51 mg, 0.32 mmol) and (E)-2-[8-(bromomethyl)-2,3-difluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.32 mmol) obtained in Reference Example 3, and in the same manner as in Reference Example 1A, the title compound (132 mg, 91%) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C@H:9]1[CH2:37][C@@:36]2([CH3:38])[C@@H:20]([CH2:21][C@H:22]([CH3:46])[C@:23]2([O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31])[OH:26])[C@H:19]2[C@@:10]1([F:49])[C@:11]1([CH3:48])[C:16]([CH2:17][CH2:18]2)=[CH:15][C:14](=[O:47])[CH:13]=[CH:12]1.[NH:50]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C@H:51]([C:53]([NH:55][C@H:56]([C:58]([N:60]1[CH2:67][CH2:66][CH2:65][C@H:61]1[C:62](O)=[O:63])=[O:59])[CH3:57])=[O:54])[CH3:52].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[F:49][C@:10]12[C@@H:9]([OH:8])[CH2:37][C@@:36]3([CH3:38])[C@@H:20]([CH2:21][C@H:22]([CH3:46])[C@:23]3([O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:24](=[O:35])[CH:25]([O:27][C:28](=[O:34])[C@H:29]([CH:30]([CH3:32])[CH3:31])[NH:33][C:62](=[O:63])[C@@H:61]3[CH2:65][CH2:66][CH2:67][N:60]3[C:58](=[O:59])[C@H:56]([CH3:57])[NH:55][C:53](=[O:54])[C@H:51]([CH3:52])[NH:50][C:68]([O:70][C:71]([CH3:72])([CH3:73])[CH3:74])=[O:69])[OH:26])[C@@H:19]1[CH2:18][CH2:17][C:16]1[C@:11]2([CH3:48])[CH:12]=[CH:13][C:14](=[O:47])[CH:15]=1
Reactant: CCCCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](N)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CCCCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
1.04 g (1.50 mmol) of H-Val-O-BMV x TFA (Example 37), 500 mg (1.40 mmol) of Boc-Ala-Ala-Pro-OH and 168 mg (1.40 mmol) of Nhydroxybenzotriazole are dissolved in this sequence in 50 ml of dichloromethane, and 330 μl (3.00 mmol) of N-methylmorpholine is added. Then, a solution of 289 mg (1.40 mmol) of dicyclohexylcarbodiimide in 2 ml of dichloromethane is added and stirred for 20 hours at room temperature. Then, it is suctioned off from precipitated urea, the filtrate is concentrated by evaporation and filtered again. Chromatography of this amount of raw material (300 g of silica gel, hexane/acetone 1:1) yields 806 mg(63% ) of N-(N-(N-(N-((1,1-dimethyl)ethoxycarbonyl)-L-alanyl) -L-alanyl)-L-prolyl)-L-valine [9α-fluoro-11β,21-dihydroxy-16β-methyl-3,20-dioxo-17-valeroyloxy-pregna-1,4-dien-21-yl ] ester. Crystallization from dichloromethane/diisopropyl ether 542 mg (42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10]([N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([C:23](O)=[O:24])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CO.O>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH2:20][C@H:19]([C:23]([NH:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[O:24])[CH2:18]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NNc2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (1.27 g, 10.0 mmol), (S)-1-BOC piperidine-3-carboxylic acid (Alfa Aesar, 2.29 g, 10.0 mmol) and HOBt.H2O (153 mg, 1.00 mmol) in DCM (50 mL) was added EDC (2.30 g, 12.0 mmol) and the resulting orange solution stirred at RT for 16 h. Water (25 mL) was added and the mixture shaken. The aqueous was extracted with DCM (25 mL) then the combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave a pale brown foam. FCC, using 0-5% MeOH in DCM, gave the title compound as a pale orange foam (3.21 g, 95%). LCMS (Method 3): Rt 3.14 min, m/z 361 [MNa+].
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[NH:12][C:11]2=[S:21])[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:31]([S:21][C:11]1[N:10]([CH:9]2[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]2)[C:14]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=2[N:12]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OCC1CC(n2c(=S)[nH]c3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: OCC1CC(n2c(SCc3ccccc3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Temperature: 25 °C
Reaction time: 60 h
Yield: 65 %

Procedure:
A mixture of (±)-(1R*, 2S*, 3S*, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.50 g, 1.05 mmol), benzyl bromide (0.3 mL, 2.5 mmol) and anhydrous potassium carbonate (0.145 g, 1.05 mequiv as 98%) in dioxane (5 mL) was stirred vigorously at ambient temperature for 2.5 days. Volatiles were evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform layer was dried(sodium sulfate) and concentrated to an oil which was stirred in ammonia-methanol (40 mL of half-saturated) for 18 hours. Volatiles were evaporated and the residue solidified from 3:1 methanol-water to give title compound as a white powder (300 mg, 65%), m.p. 160°-162° C.; 1H-NMR(DMSO-d6)δ: 8.04 and 7.89 (both s, 1 each, 2 aromatic CH), 7.5-7.2 (m, 5, C6H5), 5.06 (t, J=4.7 Hz, 1, OH), 4.98 (d, J=6.2 Hz, 1, OH), 4.75-4.55 (m overlapping d at 4.68, J=3.7 Hz, and s at 4.63, total 4, NCH, OH, and SCH2); mass spectrum(CI): 439 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2].CS(C)=O.[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)(=O)C.C(O)(=O)C.O>[C:1]([NH:4][C:5]1([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)NC1(CCCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 0 °C

Procedure:
The process is performed as in Example 44 but starting with 3 g of (10 RS)-10-acetamido-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 70 ml of dimethyl sulphoxide, 1.2 g of an 80% suspension of sodium hydride in oil and 2.6 ml of 1-bromo-3-phenylpropane. The reaction medium is poured into a mixture of 250 g of ice, 435 ml of distilled water and 6 ml of acetic acid. 200 ml of ethyl acetate are added to the suspension obtained and the mixture is stirred, followed, after separation of the phases once settling has taken place, by removal of the ethyl acetate. The operation is repeated once. The precipitate is filtered off on a sinter funnel. The solid is crystallized from 200 ml of methanol. 390 mg of (10 RS)-10-acetamido-10-(3-phenylpropyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e)pyrazin-4-one are obtained in the form of a green solid melting above 260° C. (Analysis, % calculated C: 72.3, H: 5.6, N: 14.0; % found C: 72.2, H: 5.5, N: 14.2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:24]/[O:25][C:26]([C:29]([O:31]C(C)(C)C)=[O:30])([CH3:28])[CH3:27])/[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([OH:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1.FC(F)(F)C(O)=O>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:24]/[O:25][C:26]([C:29]([OH:31])=[O:30])([CH3:27])[CH3:28])/[C:8]([NH:10][C@H:11]2[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]([S:19]([OH:22])(=[O:21])=[O:20])[C:12]2=[O:23])=[O:9])[N:6]=1
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reaction time: 0.75 h
Yield: 5.5 %

Procedure:
550 mg of rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid are added at room temperature to 5.5 ml of trifluoroacetic acid. After 45 minutes, the mixture is evaporated and the residue is purified by chromatography on reverse-phase silica gel using water/methanol (4:1). There are obtained 27 mg of pure rac-cis-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino]acetamido]-4-methoxycarbonyl-2-oxo-1-azetidinesulphonic acid as an amorphous lyophilizate.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:11][C:10]=1[C:19]([OH:21])=O)=O)(C)(C)C.[NH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([NH:35]C(=O)OC(C)(C)C)[CH2:30]1>>[NH2:8][C:9]1[S:13][C:12]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:11][C:10]=1[C:19]([NH:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([NH2:35])[CH2:30]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(C2CCCC2)nc1C(=O)O
Product: Nc1sc(C2CCCC2)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Yield: 48 %

Procedure:
Followed the procedure as described in EXAMPLE 1, starting with 5-(tert-butoxycarbonylamino)-2-cyclopentylthiazole-4-carboxylic acid and (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate. Obtained the desired product as a white solid (22 mg, 48%). 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.24 (s, 1H), 7.10 (d, J=5.3 Hz, 1H), 3.23 (m, 3H), 3.07 (d, J=10.5 Hz, 1H), 2.96 (d, J=9.7 Hz, 2H), 2.67-2.53 (m, 2H), 2.43-2.34 (m, 1H), 2.03 (d, J=8.1 Hz, 2H), 1.87 (d, J=12.5 Hz, 1H), 1.84-1.58 (m, 5H), 1.17 (d, J=13.3 Hz, 1H). ESIMS m/z=387.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:20]([C:30]([OH:32])=O)=[C:19]([CH3:33])[NH:18][C:17]=2[CH3:34])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:42][CH2:43][NH2:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.Cl.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>ClCCl.O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH3:34])=[N:18][C:19]([CH3:33])=[C:20]([C:30](=[O:32])[NH:44][CH2:43][CH2:42][CH:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:21]=2[C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)C(c2cc(Cl)cc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg (0.588 mmol) of 4-[5-carboxy-4-(3,5-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid t-butyl ester, 0.12 ml (0.882 mmol) of 3,3-diphenylpropylamine and 248 mg (1.29 mmol) of WSC hydrochloride were stirred in 15 ml of dichloromethane and 1 ml of DMF at room temperature overnight. After dichloromethane was evaporated under reduced pressure, ethyl acetate was added. After being washed with saturated aqueous sodium hydrogencarbonate solution and 1 N hydrochloric acid, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in 8 ml of acetone. 811 mg (1.48 mmol) of diammonium cerium nitrate (IV) suspended in 8 ml of water was dropped and stirred at room temperature for 1 hour. After acetone was evaporated under reduced pressure, ethyl acetate was added. After being washed with water, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1 to 80/1) to obtain the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33](=[N:42][C:43]#[N:44])OOC3C=CC=CC=3)[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:45]1([NH2:51])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(O)(C)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33]([NH:51][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[N:42][C:43]#[N:44])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: NC1CCCCC1
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CC(C)O
Product: CCCc1nc2c(C)cc(NC(=NC#N)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1c from 4'-[[2-n-propyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol-1-yl] -methyl]-2-(1H-tetrazol-5-yl)-biphenyl and cyclohexylamine in boiling isopropanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([C:18]1([NH2:38])[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]([CH3:36])[C:19]1=[O:37])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([C:18]2([NH2:38])[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]([CH3:36])[C:19]2=[O:37])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Example 8-I), the title compound was prepared as a white solid having a melting point of 185-188° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][N:24]([CH3:34])[CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][N:31]([C:4]([C:3]2[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=2[F:1])[CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[O:6])[CH2:30][CH2:29]1
Reactant: CN(C)CCOC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 28.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), N,N-dimethyl-2-(piperidin-4-yloxy)ethanamine (85) (0.116 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.087 g, 28.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.62-1.51 (1H, m), 1.84-1.66 (3H, m), 1.95-1.89 (1H, m), 2.28 (6H, s), 2.52 (2H, t), 3.15-3.01 (1H, m), 3.48-3.40 (1H, m), 3.62-3.51 (3H, m), 4.07-3.98 (1H, m), 4.27 (2H, s), 7.01 (1H, t), 7.32-7.25 (2H, m), 7.77-7.70 (3H, m), 8.47-8.45 (1H, m), 10.62 (1H, s); m/z (LC-MS, ESI+), RT=1.67 (M+H 452).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]1[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=1[Cl:12])[CH3:5].CC(C[AlH]CC(C)C)C>CCOCC>[Cl:12][C:11]1[C:6]([CH:4]([CH3:5])[CH2:3][OH:2])=[C:7]([Cl:13])[N:8]=[CH:9][N:10]=1
Reactant: COC(=O)C(C)c1c(Cl)ncnc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: CC(CO)c1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of 2-(4,6-Dichloro-pyrimidin-5-yl)-propionic acid methyl ester (0.5 g, 2.13 mmol) in ether (40 mL) at −78° C. was added DIBAL-H (1.5M, 4 mL, 6.0 mmol) dropwise. The mixture was allowed to warm up to room temperature and stirred for 3 hours. Then quenched with 2N HCl (10 mL) at −78° C. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (4:1) to give 2-(4,6-Dichloro-pyrimidin-5-yl)-propan-1-ol (0.40 g, 91%). 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 4.16 (m, 1H), 3.90 (m, 2H), 1.93 (s, 1H), 1.40 (d, J=7.2 Hz, 3H).