Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16](O)=[O:17].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:6]=[CH:5][C:4]=1[C:16]([NH2:23])=[O:17]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid (5.0 grams, 0.015 mole) and carbonyldiimidazole (2.74 grams, 0.017 mole) were dissolved in 35 ml of DMF. The solution was stirred for 10 minutes and ammonium hydroxide (8 ml) was then added. The reaction mixture was stirred at room temperature for 72 hours, then poured into 150 ml of ice/water. The product precipitated and was separated by filtration, dried, and recrystallized from toluene with charcoal, yielding 3.0 grams of 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxamide, mp=191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:35][I:36]>C1C=CC=CC=1.CO>[I-:36].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N+:31]([CH3:35])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CI
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Solvent: c1ccccc1
Solvent: CO
Product: C[n+]1ccc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)cc1
Product: [I-]
Yield: 58 %

Procedure:
In a mixed solvent of benzene (10 ml) and methanol (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[4-(pyridin-4-yl)benzoyl]piperazine (300 mg) obtained in Example 1 was dissolved at room temperature, followed by the addition of methyl iodide (1 ml). To the resulting mixture, the same amount of methyl iodide was added three times at intervals of 24 hours, followed by heating under reflux for 4 days. The reaction mixture was distilled under reduced pressure and the residue was washed with methanol, collected by filtration and dried, whereby the title compound (229 mg, 58%) was obtained as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C(C)=CC=CC=1>[ClH:19].[ClH:19].[ClH:19].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Cl
Product: c1ccc(N2CCN(CCN3CCCC3)CC2)nc1

Procedure:
A mixture of 12 grams; (0.074 moles) of 1-(2-pyridyl)piperazine, 10.2 grams (0.074 moles) of potassium carbonate, and N-(2-chloroethyl)pyrrolidine (10.0 grams; 0.074 moles) in 80 cc xylene is boiled for about 10 hours. After cooling, the mixture is filtered and the filtrate is evaporated under reduced pressure. The oily residue is dissolved in diethyl ether and the solution after cooling is treated with gaseous hydrochloride, thus obtaining the precipitation of the trihydrochloride salt, which is recrystallized until pure: melting point 294°-296° (from methanol); Rf=0.33 (MeOH-conc. NH4OH 97:3); I.R. (nujol), νmax: 2650, 2550, 2420, 2350, 1640, 1610, 1540, 1450, 1440, 1300, 1270, 770 cm-1.Cl- (AgNO3)-calc. % 28.76--Found % 28.85.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][N:10]([CH:12](OC)OC)[CH3:11]>>[CH3:9][N:10]([CH:12]=[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1C(=O)CCCC1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of cyclohexane-1,3-dione (33.6 g, 300 mmol) in DMF-DMA (120 ml) was heated to 100° C. and stirred for 1 h under nitrogen protection. The volatiles were concentrated under reduced pressure. The red solid (55 g crude) was used in the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl.[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH2:46])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34].CN1CCOCC1>C1COCC1>[CH2:33]([O:35][C:36](=[O:47])[CH:37]([NH:46][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(N)C(=O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)c1cc2cc(Cl)ncc2[nH]1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 0.51 mmol) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (183 mg, 0.66 mmol) were dissolved in THF (20 ml). After 5 min, 2-amino-3-oxo-3-phenylpropionic acid ethyl ester hydrochloride (Tetrahedron Lett., 1993, 34(2), 211–214; 124 mg, 0.51 mmol) and 4-methylmorpholine (56 μl, 0.51 mmol) were added and the reaction mixture stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between water (40 ml) and EtOAc (3×30 ml). The combined organics were dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:19). This material was further triturated with methanol:diethyl ether (1:19) to give the title compound as a pale yellow solid. m/z (ES+)=386 [M+H]+; RT=3.56 min.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([OH:16])([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN(C)C=O.[H-].[Na+].CI>C1C=CC=CC=1>[OH:16][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]1
Reactant: COC1(OC)CCC(O)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CI
Product: O=C1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 21.65 g. (0.085 mole) of 4-hydroxy-4-(p-fluorophenyl)cyclohexanone dimethyl ketal (prepared as in Example 25) in 80 ml. of dimethylformamide and 320 ml. of benzene, 3.56 g. of 57% sodium hydride is added. Following about 1 hour of stirring at room temperature, 35 ml. of methyl iodide is added and the mixture heated at reflux. After about 4 hours of heating an additional 10 ml. of methyl iodide is added. At the end of about 18 hours of heating, the suspension, after cooling, is washed with water and brine. The organic layer is evaporated to dryness and the gum remaining dissolved in 400 ml. of acetone, then 40 ml. of 2.5N hydrochloric acid added. At the end of about 4 hours, most of the solvent is removed under vacuum. The residue is extracted with ether and the organic layer washed with aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residual gum is chromatographed on a 2 l. column of Florisil (synthetic magnesium silicate), with elution by 2 l. of Skellysolve B, 2 l. of 95% Skellysolve B:5% acetone and 4 l. of 70% Skellysolve B:30% acetone. Crystalline fractions of first the product, then 6.87 g. (49%) of 4-hydroxy-4-(p-fluorophenyl)-cyclohexanone, melting at 108° to 114° C., are obtained. The product is recrystallized from petroleum ether to give 7.76 g. (41%) of 4-methoxy-4-(p-fluorophenyl)cyclohexanone, melting at 60° to 69° C. The analytical sample melts at 68° to 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10].OS(O)(=O)=O.O=S(=O)=O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(Cl)cc1
Agent: O=S(=O)=O
Product: Nc1ccc(Cl)c(S(=O)(=O)O)c1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
128 parts of p-chloroaniline are added, in portions, at a maximum temperature of 85° C. to 238 parts of 100% sulfuric acid. The mixture is then stirred for 15 minutes at 65° C. until a clear solution forms. This sulfuric acid solution is run into 420 parts of 66% oleum over 30 minutes, while keeping the temperature at 65°-70° C. by cooling with an ice bath. The reaction mixture is stirred for 2 hours at 70° C. to bring the reaction to completion and to give 4-chloroaniline-3-sulfonic acid. The batch is then heated to 160° C. and stirred for 3 hours at this temperature. After cooling to 50° C., the sulfonation mixture is poured into 1100 parts of ice/water, and the resulting clear solution is partially neutralised with 400 parts of a 50% solution of potassium hydroxide. The monopotassium salt of 4-chloroaniline-2,5-disulfonic acid slowly precipitates and is filtered with suction and dried under vacuum, affording 260 parts of 62.0% 4-chloroaniline-2,5-disulfonic acid, corresponding to a yield of 56%, based on p-chloroaniline. The purity is >97% (analysis by HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:31])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Temperature: 120 °C
Yield: 148.3 %

Procedure:
A mixture of (R)-2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80.0 g, 272.0 mmol) and Lawesson's Reagent (66 g, 163.0 mmol) in toluene (1 L) was heated at 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3% EtOAc in petroleum ether) to give (R)-2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.0 g, 89%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.06 (dd, J=2.4, 8.8 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.71 (m, 1H), 5.06 (d, J=15.6 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H), 1.76 (d, J=7.6 Hz, 3H), 1.28-1.21 (t, J=7.2 Hz, 3H). SFC (Table 2, Method 3) Rt=4.04 min.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C@@H:2]1[CH2:8][CH2:9][CH2:10][N:30]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:7]
Reactant: CCOC(=O)C(Br)CCCBr
Reactant: CCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCCCCCN1CCC[C@H]1C(=O)OCC

Procedure:
In 150 ml of ethanol was dissolved 22.8 g of ethyl 2,5-dibromovalerate, and 15 g of potassium carbonate was suspended in the solution. To the suspension was added dropwise a methanolic solution of 18.5 g of laurylamine under ice-cooling. After the addition, the reaction mixture was allowed by react at a refluxing temperature of methanol for 5 hours to obtain N-dodecylproline ethyl ester.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].Cl.[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][SH:28])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[OH2:9].[ClH:12].[ClH:10].[C:1]1([NH:7][C:8](=[SH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O
Product: OC(Nc1ccccc1)=[SH]CCCN1CCN(CCc2ccc(Cl)cc2)CC1
Yield: 87.4 %

Procedure:
The procedure described in Example 2 was followed, using 1.6 g of phenyl isocyanate, 5.0 g of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride, 1.3 g of triethylamine and 50 ml of methylene chloride, to give 3.0 g (44% of theory) of N-phenyl-S-{3-[4-(4-chlorophenethyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride monohydrate as a white crystalline solid, M.p. 237°-239° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:22]1([C@H:28]([CH2:30][OH:31])[NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[OH:31][CH2:30][C@H:28]([NH:29][C:1](=[O:7])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: C=CCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CO)c1ccccc1
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a solution of 4-pentenoic acid (2.55 mL, 25.0 mmol) in DMF (312 mL) cooled in an ice/water bath was added HOBt (3.37 g, 25.0 mmol) and EDC (4.79 g, 25.0 mmol) and the resulting solution was stirred for 30 min (R)-(−)-2-phenylglycinol (3.43 g, 25.0 mmol), iPr2NEt (17.8 mL, 100 mmol), and DMAP (0.305 g, 2.50 mmol) were subsequently added and the reaction mixture was stirred 16 h at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous layer was extracted 2× with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 3.5 g of product as a colorless oil in 64% yield. LRMS (M+H)+: 220.1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([F:57])=[C:10]([CH:16]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([NH2:56])=[N:47]C(=O)C3C=CC=CC=3)=[CH:42][CH:41]=2)[C:17]2[N:18]=[C:19]([O:28][CH2:29][O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[CH2:33][O:34][CH3:35])[N:20]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:21]=2)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)(=[O:3])[CH3:2].CO>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([F:57])=[C:10]([CH:16]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([C:46](=[NH:47])[NH2:56])=[CH:42][CH:41]=2)[C:17]2[N:18]=[C:19]([O:28][CH2:29][O:30][C:31](=[O:38])[C:32]([CH3:37])([CH3:36])[CH2:33][O:34][CH3:35])[N:20]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:21]=2)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Solvent: CC(=O)O
Solvent: CO
Product: COCC(C)(C)C(=O)OCOc1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)cc(OCCOC(C)=O)c2F)nn1-c1ncccn1
Temperature: 40 °C
Reaction time: 15 h
Yield: 168.1 %

Procedure:
Under nitrogen atmosphere, a mixture of 3-methoxy-2,2-dimethylpropionic acid 5-[[3-(2-acetoxyethoxy)-2-fluoro-5-methoxyphenyl]-(4-{amino[benzoylimino]methyl}phenylamino)methyl]-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester (184 mg), methanol (10 mL), and acetic acid (1 mL) was stirred at 40° C. for 15 hours. Under reduced pressure, the solvent in the mixture was distilled off. The residue obtained was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water, containing 0.1% of acetic acid) to obtain the captioned compound (146 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26]Cl)[CH:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C-:32]#[N:33].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][C:32]#[N:33])[CH:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCC#N
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-chloroethyl)indolin-5-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) in ethanol (0.8 mL) and water (0.4 mL) were added NaCN (22 mg, 0.45 mmol) and KI (cat) at room temperature. The reaction mixture was stirred for 30 min at 110° C. in the microwave before being purified by column chromatography on silica gel (5-15% ethyl acetate/hexanes) to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2-cyano-ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 77%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:29])[C:16]=2[CH:15]=1>C(O)C.C1COCC1>[CH3:13][C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:29])[C:16]=2[C:15]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1c(C)ccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
Na metal (425 mg, 21.3 mmole) was dissolved in 50 mL of ethanol. To 5 mL of this solution, diethyl malonate (32 mg, 199 μmole) in 5 mL of THF was added, and the mixture was refluxed for 1 hour. 2-bromomethylanthraquinone (Compound 4.1) (50 mg, 166 μmole) in 5 mL of THF was then added to the refluxing reaction mixture. The reaction was refluxed for 8 hours, cooled to room temperature, and then quenched with 5 mL of saturated NH4Cl solution. The mixture was concentrated under vacuum, and redissolved in 20 mL of ethyl acetate for H2O extraction. The organic layer was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography to yield 41 mg (54 %). 1H NMR (300 MHz, CDCl3) δ 8.11 (2H, m), 7.96 (1H, s), 7.88 (1H, d), 7.64 (1H, d), 7.37 (2H, m), 4.61 (2H, d), 4.20 (5H, m), 1.21 (6H, t).
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([C:9]1([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccccc2N1N1CCCCC1
Reactant: ClCc1ccccc1
Product: O=C1N(N2CCCCC2)c2ccccc2C1(Cc1ccccc1)Cc1ccccc1

Procedure:
By substituting 1,3-dihydro-1-(1-piperidinyl)-2H-indol-2-one and benzyl chloride in Example 8, the desired product was obtained; m.p. 94°-96° C. (hexane). Anal. (C27H28N2O): C, H, N.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.C1COCC1>[CH3:1][S:2][C:3]1[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29]([NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: CSc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1cnc(-c2ccc(NC(=O)Nc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 30.3 %

Procedure:
A mixture of 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)benzeneamine (0.1 g, 0.33 mmole), co-solvent (5 ml, DMF/THF=6/40) and phenyl isocyanate (0.2 ml, 0.92 mmole) was heated to 80° C. After 12 hrs, the reaction mixture was cooled, and the THF removed in vacuo. Then the mixture was diluted with EA, washed with brine, and dried (MgSO4). The solvent was removed in vacuo. Purification of the residue on silica gel (EA/Hex=1/2) yielded the desired compound (42.2 mg, 30.4%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH:24]1([C@H:30]([NH2:32])[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C@H:30]([NH:32][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:2])[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C[C@@H](N)C1CCCCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: C[C@@H](NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2)C1CCCCC1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-[4-carboxybicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and (1R)-1-cyclohexylethylamine (49.7 μL) were used to obtain (2S,4S)-1-[[N-(4-[-N-[(1R)-1-cyclohexylethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (29.9 mg).
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44](O)=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.O1CCOCC1>[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 2 h
Yield: 74 %

Procedure:
23 g (0.086 mol) of prolyl-arginine (2) are dissolved in 100 ml of water and to this solution under stirring there is added a solution of 53 g (0.1 mol) of pentafluorophenyl ester of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysine in 300 ml of dioxane. 2 hours thereafter the solvent is evaporated and the residue is dissolved in 150 ml of dimethylformamide and stirred at room temperature (20° C.) for 48 hours. Then dimethylformamide is evaporated to 1/3 of its volume and the solution is poured into one liter of ether. After 2 hours the resulting residue is filtered-off, washed on the filter with ether and dried in vacuum. After reprecipitation from a mixture ethylacetate-ethanol-ether (3:1:30) there are obtained 47 g (74%) of the product (3) having the following properties: M.p. 90° C., [α]D20 -39.0° (c 1.0; 10% CH3COOH); Rf =0.51 (A, "Eastman"), 0.82 (B, "Eastman"); EHis =0.34 (pH=2.4).