Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][S:7]([C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:38])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)NCCS(=O)C1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 60 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, in 10 mL of methylene chloride at -50° under argon was added a solution of 32 mg of m-chloroperbenzoic acid in 3 mL of methylene chloride in one portion. This solution was stirred for 30 min at -40° and then allowed to warm to room temperature over a 30 min period. The methylene chloride solution was washed sequentially with aqueous sodium sulfite and aqueous sodium bicarbonate (2X), dried over sodium sulfate and evaporated to dryness. The crude product was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate, eluted with 5% methanol in methylene chloride, to afford 55 mg (88%) of 3-(2'acetamidoethylsulfinyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, as a glassy mixture of 2 diastereoisomers (at sulfur). IR (Nujol mull): 3250, 1785, 1715, 1670 cm-1 ; NMR (220 MHz; CDCl3): δ 1.93 (3H, s), 2.8-3.7 (9H, m), 4.66 (1H, m), 5.5-5.75 (2H, m), 6.48 (1H, m), and 7.3-1.1 (7H, m); MS (field desorption) confirmed molecular weight of 425. ##STR23##
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:21]([O:23]C)=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:21]([OH:23])=[O:22])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C)c(C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoate (8d) (4.08 g, 10.0 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) in a mixture of water (20 mL) and methanol (MeOH) (5 mL) is stirred at room temperature. The reaction is monitored by TLC and/or LC/MS to completion. The solvent is partially removed under reduced pressure using a rotary evaporator. The pH of the residue is adjusted to ˜1-2 with a 10.0M hydrochloric acid (HCl). The aqueous phase is extracted with ethyl acetate (4×) and the combined organic extracts are washed with and brine, dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents removed under reduced pressure using a rotary evaporator to yield the target compound 3-[3-tert-butoxy-1-[(tert-butoxycarbonylamino)methyl]-3-oxo-propyl]-4-methyl-benzoic acid (8e), which can be used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:39])([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:4]([OH:40])=[O:3])=[CH:12][CH:11]=2)[N:17]([CH3:31])[C:18]1=[O:30]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cccc(OC)c3)C(=O)N2C)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccccc4)C(=O)O)cc3)N(C)C2=O)c1
Yield: 97.2 %

Procedure:
A solution of 3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.28 g, 0.51 mmol) in ethanol (20 mL) is treated with aqueous 5 N NaOH (2 mL) and heated to reflux 1 h. The reaction mixture is cooled, the solvent removed in vacuo. The resultant residue is acidified with aqueous 1 N HCl (20 mL) and extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to afford 0.257 g (97%) 3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid 1H NMR (500 MHz, CDCl3) □ 7.28-7.20 (m, 3H), 7.18 (d, 2H, J=8.80 Hz), 7.04 (t, 1H, J=7.34 Hz), 6.91 (d, 2H, J=7.83 Hz), 6.82 (t, 1H, J 7.83 Hz), 6.79-6.78 (m, 2H), 6.73 (d, 2H, J=8.83 Hz), 4.38, 4.28 (ABq, 2H, J=14.92 Hz), 3.95 (t, 2H, J=5.87 Hz), 3.77 (s, 3H), 3.60 (ddd, 1H, J=12.2 Hz, J=8.40 Hz, J=3.42 Hz), 3.36 (t, 1H, J=7.83 Hz), 3.30, 3.10 (ABq, 2H, J=13.69 Hz), 2.96 (t, 1H, J=7.83 Hz), 2.83 (s, 3H), 2.25-2.18 (m, 1H), 1.92-1.84 (m, 1H), 1.42 (s, 3H). HRMS (ES+) m/z exact mass calc'd for C30H35N2O6 (M+1) 519.2495. Found m/z 519.2504.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:18]3[CH:19]=[N:20][C:21]([NH2:35])=[C:22]([O:23][C@@H:24]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[C:28]([F:33])[C:27]=4[Cl:34])[CH3:25])[C:17]=3[O:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:34][C:27]1[C:28]([F:33])=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C@H:24]([O:23][C:22]1[C:17]2[O:16][CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[C:18]=2[CH:19]=[N:20][C:21]=1[NH2:35])[CH3:25]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 4-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-3-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (98.0 mg, 0.188 mmol) in 4 M HCl in 1,4-dioxane (8 mL) was cooled to 0° C., then stirred at 50° C. for 2 h. The material was concentrated in vacuo and then extracted with DCM and sat. aq. NaHCO3. The organic layer was concentrated in vacuo to afford the title compound as a brown solid. 1H NMR (CDCl3, 400 MHz): δ=1.86 (d, J=6.8 Hz, 3H), 2.37-2.47 (m, 2H), 3.15 (t, J=5.8 Hz, 2H), 3.60 (d, J=2.8 Hz, 2H), 4.74 (s, 2H), 6.28 (br, s, 1H), 6.52 (q, J=6.7 Hz, 1H), 7.02-7.08 (m, 1H), 7.27-7.32 (m, 1H), 7.37 (s, 1H), 8.25 (s, 1H). MS (ES+): m/z 422.06 [MH+]. HPLC: tR=2.23 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[CH2:13][C:12]2=[O:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.CCOC(C)=O>[CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[CH2:13][CH:12]2[OH:23])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C1CC(O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of 8-benzyl-1-phenyl-1,8-diazaspiro[4.5]decane-2,4-dione (2.3 g, 6.85 mmol) in methanol (50 mL) was added NaBH4 (0.78 g, 20.5 mmol) in portions at 15° C. The mixture was stirred for 1 h at 15° C. H2O (5 mL) was added slowly at 0° C. The solvent was removed under reduced pressure to give crude product, which was dissolved in EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give 8-benzyl-4-hydroxy-1-phenyl-1,8-diazaspiro[4.5]decan-2-one, which was used directly in the next step.
Reaction SMILES: I.[NH:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1.[H-].[Li+].[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N:19]=[C:20]=[O:21])[CH3:11]>CN(C)C=O>[CH2:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20]([N:2]=[C:3]1[NH:7][CH2:6][CH2:5][NH:4]1)=[O:21])[CH3:11]
Reactant: N=C1NCCN1
Reactant: CCc1cccc(C)c1N=C=O
Agent: I
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCc1cccc(C)c1NC(=O)N=C1NCCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a manner similar to that previously described, 15.55 grams (0.073 mole) of 2-iminoimidazoline hydroiodide is added dropwise to a dry cooled suspension of 596 milligrams (0.075 mole) of lithium hydride in 30 milliliters of dimethylformamide under an atmosphere of nitrogen. After completion of the addition, the mixture is allowed to warm to room temperature to complete the reaction. Thereafter the mixture is again cooled, a solution of 8.1 grams (0.05 mole) of 2-ethyl-6-methylphenyl isocyanate in 25 milliliters of dry dimethylformamide is added dropwise over a two hour period and thereafter the resulting mixture is stirred overnight while the temperature is allowed to rise to ambient temperatures to obtain a N-(2-ethyl-6-methylphenyl-N'-(2-imidazolidinylidene)urea product. The base product is recovered by procedures similar to that previously described and after recrystallization from methanol-water, a purified base product, m.p. 185°-187° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[C:10]#[C:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Li+].[Cl-].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH3:9])[C:3]=2[C:10]#[C:11][C:12]2[CH:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:21][C:20]=1[F:19]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CCc1nccc(Cl)c1C#Cc1ccc(N)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: O
Product: CCc1nccc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 3.2 g (12.3 mmol) 5-(4-Chloro-2-ethyl-pyridin-3-ylethynyl)-pyridin-2-ylamine (A-30) using 3.6 g (18.4 mmol) 3-Fluoro-4-methoxycarbonylphenyl boronic acid, 561 mg (0.61 mmol) Pd2(dba)3, 877 mg (1.84 mmol) X-Phos, 519 mg (12.3 mmol) LiCl and 3.39 g (14.7 mmol) K3PO4 in a mixture of 60 mL 1,2-dimethoxyethane and 10 mL water. The reaction mixture is stirred for 16 h at 95° C. After completion of the reaction, the mixture is poured into water and the formed precipitate is collected by filtration. The product is purified by chromatography on silica gel using an DCM/MeOH-mixture (3% MeOH, flow 55 mL/min). Yield: 2.46 g (53%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=O)[C:13]2[CH:23]=[CH:24][CH:25]=[N:26][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>N1C=CC=CC=1>[CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[S:28])[C:13]2[CH:23]=[CH:24][CH:25]=[N:26][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)CC(=O)N1c2ccccc2NC(=O)c2cccnc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCN(CCC)CC(=O)N1c2ccccc2NC(=S)c2cccnc21

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-[(dipropylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:23]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH2:4].Cl.C(N(CCCC)CCCC)CCC.[Cl:19][CH2:20][CH2:21][N:22]([CH2:32][CH2:33][Cl:34])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CCOCC.CN(C)C=O.CCCCCC>[Cl:19][CH2:20][CH2:21][N:22]([CH2:32][CH2:33][Cl:34])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:4][CH2:3][CH2:2][Cl:1])=[O:31])=[CH:27][CH:28]=1
Reactant: NCCCl
Reactant: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(NCCCl)Nc1ccc(N(CCCl)CCCl)cc1
Temperature: 34 °C
Yield: 86.3 %

Procedure:
A mixture of β-chloroethylamine.HCl (5.80 g, 0.05 mole), hexane (60 ml), N,N-dimethylformamide (30 ml) and tributylamine (14.83 g; 0.08 mole) was cooled to -10° C., and an ether solution (100 ml) of p-bis(β-chloroethyl)aminophenyl isocyanate (12.9 g; 0.05 mole) was added with stirring. One hour later, the reaction mixture was heated at 34° C. for 6 hours. Low-boiling fractions were removed by distillation under reduced pressure. The residue was poured into ice water (500 ml), and the resulting white solid was collected by filtration and dried to give N-[p-bis(β-chloroethyl)aminophenyl]-N'-(β'-chloroethyl)urea (14.61 g). The yield was 86.3%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:7]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Oc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc(Br)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a solution of 5-bromopyridin-2-ol (0.250 g, 1.437 mmol) in DMF (1.50 mL) at 0° C., was added NaH (60% in mineral oil, 0.075 g, 1.868 mmol) portion-wise over a period of 10 min. The mixture was warmed to room temperature and stirred for 30 min. To the mixture was added methyl 3-(bromomethyl)benzoate (0.395 g, 1.724 mmol) in one portion. The reaction was stirred at room temperature for 16 h and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.274 g, 59% yield) as clear pale-yellow oil. LCMS, [M+H]+=322.0. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.37 (d, J=2.7 Hz, 1H), 7.33 (dd, J=9.7, 2.7 Hz, 1H), 6.52 (d, J=9.7 Hz, 1H), 5.11 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:13].[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1)=[O:26]>>[CH3:23][CH:24]([CH3:40])[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:13])[CH2:36][CH2:35]2)[CH:29]=1)=[O:26]
Reactant: O=C(CCCCCl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 5-chloro-1-(4-nitrophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 452.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O[CH:12]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1cccc(O)c1
Product: CC(=O)c1cccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 526.9 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([CH:29]([CH2:33][CH2:34][CH3:35])[C:30](Cl)=[O:31])[CH2:27][CH3:28]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:30](=[O:31])[CH:29]([CH2:33][CH2:34][CH3:35])[CH2:26][CH2:27][CH3:28])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(CCC)C(=O)Cl
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CCCC(CCC)C(=O)N[C@@H](CC(C)C)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Yield: 60 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (20 mg) with di-n-propylacetyl chloride(14 uL) provided 16 mg (60%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1>C(O)CCC>[CH2:2]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1C=CC(O)N1
Solvent: CCCCO
Product: CCCCOC1C=CC(=O)N1
Temperature: 70 °C
Yield: 199.2 %

Procedure:
A mixture of 2.5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 75 cm3 of 1-butanol and 1.3 g of Amberlite IR 120 H is heated to 70° C. for 2 hours. After allowing to return to ambient temperature, the residue is filtered and the solvent is evaporated under reduced pressure. 3.9 g of the expected product is obtained.
Reaction SMILES: C1(C2C(N3CCN(C(C4C=NC(F)=CC=4C)=O)CC3)=NC=C(C)C=2)CC1.COC1C=CC(CN)=CC=1.Cl[CH2:38][CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].[NH2:45][C:46]1[N:51]=[CH:50][C:49]([C:52]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[C:65]([CH:66]4[CH2:68][CH2:67]4)=[CH:64][C:63]([CH3:69])=[CH:62][N:61]=3)[CH2:56][CH2:55]2)=[O:53])=[C:48]([CH3:70])[CH:47]=1>>[CH:66]1([C:65]2[C:60]([N:57]3[CH2:58][CH2:59][N:54]([C:52]([C:49]4[CH:50]=[N:51][C:46]([N:45]5[CH2:38][CH2:39][CH2:40][S:41]5(=[O:43])=[O:42])=[CH:47][C:48]=4[CH3:70])=[O:53])[CH2:55][CH2:56]3)=[N:61][CH:62]=[C:63]([CH3:69])[CH:64]=2)[CH2:68][CH2:67]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C2CC2)c1
Agent: COc1ccc(CN)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cc3C)CC2)c(C2CC2)c1

Procedure:
Using [4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (180 mg) described in Preparation Example 181, 4-methoxybenzylamine (2 mL) and 3-chloropropane-1-sulfonyl chloride (0.12 mL) and by the reaction and treatment in the same manner as in Example 229, the title compound (125 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:10])[CH3:19]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 4′-methoxyacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:19])[C:13]([CH2:17]Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([Cl:19])[C:13]([CH2:17][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CBr)ccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A mixture of 316 (16.1 g, 0.0467 mol) and potassium phthalimide (26.1 g, 0.141 mol) in anhydrous DMF (150 mL) was stirred at 80° C. overnight. The cooled reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 20% EtOAc) to afford 10.8 g (56%) of tert-butyl-4-chloro-5-((1,3-dioxoisoindolin-2-yl)methyl)-1H-indole-1-carboxylate (318) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.2 Hz, 1H), 7.88-7.86 (m, 2H), 7.74-7.72 (m, 2H), 7.62 (d, J=3.7 Hz, 1H), 7.27-7.25 (m, 2H), 5.12 (s, 2H), 1.65 (s, 9H).