Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:27])[CH2:12][O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([O:23][C:24](Cl)=[O:25])[CH:20]=[CH:21][CH:22]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)C.O>[CH3:10][CH:11]([CH3:27])[CH2:12][O:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([O:23][C:24](=[O:25])[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)=[O:15]
Reactant: CC(C)COC(=O)Nc1cccc(OC(=O)Cl)c1
Reactant: CNc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)Nc1cccc(OC(=O)N(C)c2ccc(Cl)cc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 14.2 g (0.1 mole) 4-chloro-N-methylaniline in 100 ml acetic acid ethyl ester is mixed with 50 ml water. Then a solution of 27.2 g (0.1 mole) chloroformic acid-3-(2-methylpropoxycarbonylamino)-phenyl ester in 100 ml acetic acid ethyl ester and simultaneously a solution of 13.8 g (0.1 mole) potassium carbonate in 50 ml water is added in drops within 20 minutes while agitating and cooling to 10° to 15° C. Agitation is continued at 15° C. for another 30 minutes. Then the organic phase is separated, washing at 0° C. with dilute soda lye, dilute hydrochloric acid and water. Drying with magnesium sulfate is followed by evaporation under reduced pressure. Recrystallization from acetic acid ethyl ester/pentane.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[C:20]([O:24][C:25](=[O:38])[CH:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:20]([O:24][C:25](=[O:38])[CH:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4=[N:1][S:2][N:3]=[C:4]4[CH:9]=3)=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:15])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.27) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid and (+)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.[Br-]>CN(C=O)C.O>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:29][CH:28]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
60% mineral oil suspension of sodium hydride (1.454 g; 36.3 mmol) was added into anhydrous DMF (50 mL) under nitrogen at 0° C. Diethyl malonate (5.82 g; 36.3 mmol) was added to the stirred suspension over 10 min and the mixture was then stirred rapidly at 0° C. until a clear pale yellow solution was obtained. 4-(bromomethyl)benzophenone (5.00 g; 18.2 mmol) in DMF (15 mL) was added dropwise over 5 min and the reaction mixture was stirred for 16 h at ambient temperature. Complete conversion of the starting bromide was confirmed by TLC. The reaction was diluted with water (400 mL) and extracted with dichloromethane (3×50 mL). The organic phase was separated, dried and evaporated to an oily residue. Chromatography on silicagel (eluent hexane/2-butanone 10:1→5:1) provided the desired 1,3-diethyl 2-[(4-benzoylphenyl)methyl]propanedioate (5.47 g; 86%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3].[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([N:28]2[CH2:33][CH2:32][CH:31]([CH2:34][OH:35])[CH2:30][CH2:29]2)[N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1nc(S(C)(=O)=O)nc(C(=O)OCC)c1OCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOc1nc(N2CCC(CO)CC2)nc(C(=O)OCC)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A solution of ethyl 6-(allyloxy)-5-(benzyloxy)-2-(methylsulfonyl)pyrimidine-4-carboxylate (1.911 g, 4.87 mmol) in THF (40 mL) was stirred with molecular sieves for 30 min. To this mixture was added piperidin-4-ylmethanol (1.683 g, 14.61 mmol) and the resulting mixture was stirred overnight at 70° C. The mixture was cooled to room temperature and diluted with ethyl acetate and washed with water followed by brine then dried (Na2SO4). Filtration followed by concentration gave a yellow oil that was purified by flash column chromatography (Biotage flash chromatography system; 0%-100%, 10 CV) to afford the title compound as a yellow oil (1.2043 g, 58% yield). 1H NMR (300 MHz, CDCl3) δ: 7.42-7.39 (2H, m), 7.35-7.27 (3H, m), 6.10-5.97 (1H, m), 5.42-5.34 (1H, m), 5.28-5.22 (1H, m), 4.91 (2H, s), 4.87-4.84 (2H, m), 4.72-4.63 (2H, m), 4.30 (2H, q, J=7.1 Hz), 3.50 (2H, t, J=5.8 Hz), 2.80 (2H, td, J=12.8, 1.8 Hz), 1.79-1.64 (3H, m), 1.28 (3H, t, J=7.1 Hz), 1.23-1.10 (2H, m).
Reaction SMILES: [NH2-:1].[Na+].N.[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>O.C1(C)C(C)=CC=CC=1>[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:4]1([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][N:16]=[C:17]([C:15]3[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:18]=[CH:17][N:1]=3)[CH:18]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Agent: c1ccc(CCCc2ccncc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: c1ccc(CCCc2ccnc(-c3cc(CCCc4ccccc4)ccn3)c2)cc1

Procedure:
In a one-liter, three-neck flask was made 0.22 mole (5.0 g sodium) of sodamide in the usual way. The ammonia was replaced with 348 cc of xylene. The mixture was brought to reflux at 138° and 299.5 g (1.52 moles) of 4-(3-phenylpropyl)pyridine was added through a dropping funnel. Hydrogen evolution began immediately. Heating was continued for five hours at 138°-153° C. until hydrogen production slowed appreciably. The reaction mixture was cooled to around 100° C. and hydrolyzed with 100 cc of water. The oil layer was separated at room temperature and distilled through a Vigreaux column to give 182.5 g (0.93 moles) of unreacted 4-(3-phenylpropyl)pyridine and 62.9 g (0.16 mole) of 4,4'-di-(3-phenylpropyl)-2,2'-bipyridyl. The yield of 2,2'-bipyridyl product, based on 4-(3-phenylpropyl)pyridine consumed, was 54.0%.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:28]=1[NH2:29]>>[F:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:28]=1[NH:29][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: Nc1c(F)cccc1F
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3c(F)cccc3F)cnc(OC)c2o1

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.10 g) and 2,6-difluoroaniline (0.093 ml). Purification by column chromatography on silica with 30% ethyl acetate in hexane plus 1% ammonia solution, followed by trituration with ether gave the title compound (0.040 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][C@H:15]([F:14])[CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC[C@H](F)C2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.8 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.4 g, 2.34 mmol), (S)-3-fluoropyrrolidine hydrochloride (0.35 g, 2.8 mmol) and 4 Å molecular sieves (2.43 g) in DCE (10 mL). The reaction mixture was stirred for 2.5 h at room temperature. Sodium triacetoxyborohydride (0.99 g, 4.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc: cyclohexane, gradient 30:70 to 100:0) to give 3-((S)-3-Fluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.342 g, 60%). 1H NMR (300 MHz, CDCl3): δ 5.34-5.10 (m, 1 H), 4.01-3.93 (m, 2 H), 3.91-3.81 (m, 2 H), 3.41-3.31 (m, 1 H), 2.94-2.67 (m, 3 H), 2.56-2.46 (m, 1 H), 2.24-2.06 (m, 2 H), 1.43 (s, 9 H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:13][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 17.4 grams (0.11 mole) of 1,4-dioxaspiro[4.5]decan-8-ol (prepared as in Step B of Example 8) and 46.2 grams (0.14 mole) of freshly recrystallized carbon tetrabromide in 100 mL of methylene chloride is cooled to about 0° C., and a solution of 32.3 grams (0.12 mole) of triphenylphosphine in 50 mL of methylene chloride is added dropwise. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. After this time the reaction mixture is concentrated to about one quarter of the original volume. The concentrate is then passed through a pad of silica gel. Elution is accomplished with heptane. The eluate is concentrated under reduced pressure, yielding 8-bromo-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2ncccc12
Product: Clc1nccc2ncccc12
Temperature: 80 °C
Yield: 87 %

Procedure:
The product from Example 36d (0.250 g, 1.71 mmol) was combined with phosphorous oxychloride (4 mL) and heated under a nitrogen atmosphere at 80° C. for 18.5 h followed by vacuum distillation to remove the volatiles. The residue was slurried with ice and made basic (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, water washed and dried under vacuum to give a gray solid (0.245 g, 87%) sufficiently pure for use as isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].N1C=CC=CC=1>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[O:10])[O:11][C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminopyridine (1.97 g, 20.9 mmol) in DCM (75 mL) at 0° C. was added 4-nitrophenyl chloroformate (4.21 g, 20.9 mmol) and pyridine (1.7 mL, 20.9 mmol). Then, the mixture was stirred at RT overnight. The white precipitated was filtered off and washed with DCM (2×50 mL), and then dried in vacuo to give the title compound as a white solid, which was used in the next step without further purification. MS (ESI, positive ion) m/z: 260 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[OH-].[Na+]>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)OCO3)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with Benzo[1,3]dioxol-5-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C20H22O7 [M+Na]+: 397, [M+H]+: 375.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:17]([C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)=[O:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:2]1([C:1]2[O:18][C:17]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)C(=O)c1ccsc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1-c1ccsc1
Yield: 78.4 %

Procedure:
5.8 g of ethyl 3-benzoylamino-3-(3-thienylcarbonyl)propionate, 30 ml of dimethylformamide and 3.8 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 4.3 g of ethyl 2-[2-phenyl-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].[CH2:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][N:29]=1)[CH3:27].C([Mg]Cl)(C)C>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([C:31]2[CH:30]=[N:29][C:28]([CH2:26][CH3:27])=[CH:33][CH:32]=2)=[O:5])=[CH:7]1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: CCc1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 300 mg (0.84 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 433 mg (1.86 mmol) of 2-ethyl-5-iodo-pyridine in 2 mL THF with 0.97 mL 2M isopropylmagnesium chloride. Yield: 127 mg of a white powder. LC-MSD, m/z for C24H19ClN2O2 [M+H]+=403.1, 405.1; HPLC retention time: 1.8 min.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[C:1]1([C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33]3[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])[CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:28]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 97 was prepared from tri phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 2H, J=10.4 Hz), 7.34–7.21 (m, 17H), 6.90 (d, 1H, J=7.6 Hz), 6.31 (t, 1H, J=5.2 Hz), 3.43 (dd, 2H, J=6.4, 12.4 Hz), 2.87 (d, 2H, J=12.0 Hz), 2.41 (m, 1H), 2.31 (m, 4H), 1.92 (t, 2H, J=11.6 Hz), 1.79–1.66 (m, 6H), 1.59–1.52 (m, 2H), 1.01 (t, 3H, J=7.2 Hz); ESMS m/e: 574.4 (M+H)+.
Reaction SMILES: N1C=CC(CNCCN)=N1.C(N=C=S)C.[CH2:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)=S)[CH3:17].[N:31]#[C:32][NH2:33].[Pb]>>[C:32]([NH:33][C:19]([NH:18][CH2:16][CH3:17])=[N:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)#[N:31]
Reactant: N#CN
Reactant: CCNC(=S)NCCNCc1cc[nH]n1
Agent: NCCNCc1cc[nH]n1
Agent: [Pb]
Solvent: CCN=C=S
Product: CCNC(=NCCNCc1cc[nH]n1)NC#N

Procedure:
By the procedure of Example 3(b), reacting N-(3-pyrazolylmethyl)ethylenediamine with ethyl isothiocyanate, then reacting the resulting N-ethyl-N'-[2-(3-pyrazolylmethylamino)ethyl]thiourea with lead cyanamide gives N-cyano-N'-ethyl-N"-[2-(3-pyrazolylmethylamino)ethyl]guanidine. By the same procedure, using propyl isothiocyanate the corresponding N'-propyl compound is prepared. Also, by the same procedure, using 2-dimethylaminoethyl isothiocyanate, the product is N-cyano-N'-(2-dimethylaminoethyl)-N"-[2-(3-pyrazolymethylamino)ethyl]-guanidine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[Cl:25][CH2:26][C:27]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cc2c(N)cccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(NC(=O)CCl)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 65 %

Procedure:
Ethyl 4-amino-N-(3,4-dichlorobenzyl)indole-2-carboxylate (2.03 g), chloroacetyl chloride (0.5 ml) and triethylamine (4.0 ml) were stirred in dichloromethane (50 ml) for 16 hours. The reaction was washed with water, dried (MgSO4) and concentrated in vacuo. The residue was triturated with toluene to give the product as a pale grey solid (1.61 g, 65%); NMR d (CD3SOCD3) 1.28 (t, 3H), 4.30 (q, 2H), 4.40 (s, 2H), 5.81 (s, 2H), 6.88 (dd, 1H), 7.30 (m, 3H), 7.50 (d, 1H), 7.76 (s, 1H), 7.78 (d, 1H), 10.19 (brs, 1H); M/z (−) 439 (M+), 4.37.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].S(C1C=CC(C)=CC=1)([O-])(=O)=O>CN(C=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:21]([NH:39][C@H:40]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:23])[CH2:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Yield: 103.3 %

Procedure:
A solution, cooled to -20° C., of 32.3 g of Boc-Asp-(OBzl)-OH in 150 ml of DMF is treated with 11 ml of N-methylmorpholine and 13.07 ml of isobutyl chloroformate. The suspension obtained is stirred at -15° C. and treated with a suspension, cooled to -20° C., of 37.95 g of H-Val-OBzl.tosylate and 11 ml of N-methylmorpholine in 150 ml of DMF. The reaction mixture is stirred at below -10° C. for 10 minutes and at room temperature for 2 hours, filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution and dried. The organic phase is concentrated. 52.9 g of Boc-Asp(OBzl)-Val-OBzl are obtained. 10.24 g thereof are dissolved in 30 ml of TFA and then concentrated. The residue, is crystallized from ethyl acetate/hexane. There are obtained 8.3 g of H-Asp- (OBzl)-Val-OBzl.TFA (1:1),.m.p. 147°-148° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15][Br:16])=[C:12]([CH2:17]Br)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C-:20]#[N:21].[Na+]>CS(C)=O>[C:1]1([CH3:19])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:11][C:12]([CH2:17][C:20]#[N:21])=[C:13]([CH2:15][Br:16])[CH2:14]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CC#N)C2)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
10 g of N-(p-toluenesulfonyl)-3,4-bis(bromomethyl)-3-pyrroline, prepared in Preparation 5, was dissolved in 10 ml of dimethylsulfoxide (DMSO) and then heated in oil bath for 2 hours with refluxing. During the heating and refluxing, 1.5 g of sodium cyanide was added by small portion. The reaction mixture was cooled to room temperature and poured into ice water and then extracted with methylene chloride (200 ml×3). The extracts were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography. 5 g of the title compound was obtained (yield 57%).
Reaction SMILES: NC1(C(NC2C=CC(C=CC([O-])=O)=CC=2)=O)CCCC1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43](/[CH:46]=[CH:47]/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42][CH:41]=1.[C:53]([O:57][C:58]([NH:60][C:61]1([C:66](O)=[O:67])[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C1COCC1>[C:53]([O:57][C:58]([NH:60][C:61]1([C:66]([NH:39][C:40]2[CH:41]=[CH:42][C:43](/[CH:46]=[CH:47]/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:44][CH:45]=2)=[O:67])[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: NC1(C(=O)Nc2ccc(C=CC(=O)[O-])cc2)CCCC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCCC2)cc1
Yield: 41 %

Procedure:
(E)-ethyl (3-(4-(1-aminocyclopentanecarboxamido)phenyl)acrylate. EEDQ (593 mg, 2.4 mmol) was added to a solution of (E)-ethyl 3-(4-aminophenyl)acrylate (417 mg, 2.18 mmol) and 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.18 mmol) in THF (6 mL). The solution was stirred at reflux for 3-4 hours. The mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was washed sequentially with dilute HCl, water, and brine. The solution was dried over Na2SO4 and filtered. Dilution of the filtrate with hexanes resulted in the crystallization of (E)-ethyl 3-(4-(1-(tert-butoxycarbonylamino)cyclopentanecarboxamido)phenyl)acrylate as a pale yellow solid (360 mg, 37% yield). ESI-MS m/z 403 (MH+).