Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CCOC(C)=O>[C:13]12([NH:12][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([Cl:11])=[N:10][C:2]=3[Cl:1])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: O=C(Cl)c1ccc(Cl)nc1Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A solution of 2,6-dichloronicotinoyl chloride (4.21 g, 20 mmol) in DCM (20 mL) was added dropwise to a stirred suspension of 1-aminoadamantane (3.03 g, 20 mmol) and N-ethyldiisopropylamine (4.19 mL, 24 mmol) in DCM (20 mL) at 0° C., over a period of 30 minutes under nitrogen. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (500 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% Et2O in DCM. Pure fractions were evaporated to dryness to afford N-adamantan-1-yl-2,6-dichloronicotinamide (5.57 g, 76%) as a white solid.
Reaction SMILES: CCCCC(N([C@H](C(O)=O)C(C)C)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22]N=NN=2)=[CH:13][CH:14]=1)=O.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1.C([O-])(=[O:51])C.[Na+]>C(O)(=O)C>[C:21]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][OH:51])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Reactant: CC(=O)[O-]
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(CO)cc1

Procedure:
According to U.S. Pat. No. 5,399,578, the process for the preparation of Valsartan (I) involves the reaction of 4′-bromomethyl-2-cyanobiphenyl (II) with sodium acetate and glacial acetic acid to produce 2′-cyano-4-hydroxymethylbiphenyl (III), which is reacted with oxalyl chloride in dichloromethane and dimethyl sulfoxide to produce 2′-cyano-4-formylbiphenyl (IV), which is further reacted with (L)-valine methyl ester hydrochloride (V) and sodium cyanoborohydride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by treatment with valeryl chloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is treated with tri-n-butyltin azide followed by flash chromatography to produce Valsartan of formula (I).
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:30][CH:29]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)=[CH:32][CH:33]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:11])[CH3:12])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Oc3cccnc3)cc2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4RS,5SR)-2-oxo-5-[4-(pyridin-3-yloxy)phenyl]-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (1.70 g, 3.02 mmol) in methanol (10 ml) was added a solution (7.26 ml, 3.63 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the objective substance (1.39 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH2:24][CH2:23]2)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7].[O:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(OCCCl)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[N:30]([CH2:47][CH2:46][O:45][CH2:49][CH3:48])[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH2:24][CH2:23]2)([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccccc3)C2)cc(OC)c1OC
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine (0.56 g, 0.77 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (1.7 mL, 0.5 M in toluene, 0.85 mmol). After 30 minutes, warm to ambient temperature. Add tetrabutylammonium bromide (0.06 g) and 2-chloroethyl ethyl ether (0.092 g 0.85 mmol). Heat to reflux. After 12 hours, potassium bis(trimethylsilyl)amide (0.5 mL, 0.5 M in toluene) and 2-chloroethyl ethyl ether (0.5 mL) and continue to reflux. After 12 hours, cool the reaction and add water. Separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.32 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][NH2:21]>C1(C)C=CC=CC=1>[CH3:19][N:20]1[N:21]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11]
Reactant: CNN
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
To a suspension of 2-(4-bromobenzoyl)benzoic acid (15.0 g, 49.2 mmol) in toluene (75 mL) at room temperature was added methylhydrazine (2.88 mL, 54.1 mmol). The reaction mixture was heated to reflux while collecting water in a Dean Stark trap for 3 hours, additional methylhydrazine (2.0 mL) was added and refluxing was continued for 15 minutes. The reaction mixture was cooled to room temperature and the product was collected by filtration and dried in vacuo to afford 13.4 g (87%) of 2-methyl-4-(4-bromophenyl)-1-(2H)-phthalazinone, m.p. 168°-170 ° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][OH:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N:8]([CH3:23])[C:9](=[O:22])[CH2:10][N:11]2[C:12](=[O:21])[C:13]3=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]3[C:15]2=[O:16])=[CH:6][CH:5]=[C:4]([Cl:24])[C:3]=1[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Reaction time: 1 h

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-(phthalimidoacetyl) amino]benzene (399 mg) and triethylamine (0.17 ml) in methylene chloride (8 ml) was added methanesulfonyl chloride (0.086 ml) under -20° C., and the mixture was stirred for 1 hour. The mixture was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo to give 2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (561 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:26][OH:27])[CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:26][O:27][CH2:2][CH2:3][OH:4])[CH3:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CC(=NO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: BrCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=NOCCO)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The target compound (3.84 g) was obtained as white crystals by carrying out the reaction and the post-treatment according to Reference examples 1(c) and 1(d) of WO 97/37970(EP 916651A) using 2-(2-bromoethoxy)tetrahydropyran (6.84 g), 4′-(4-fluorophenyl)acetophenone oxime (5.00 g), potassium carbonate (6.02 g) and a catalytic amount of p-toluenesulfonic acid monohydrate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][CH2:13]1.Br.[OH-].[K+]>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2C)CC1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1c(NC2CCNCC2)nc2ccccc21
Reaction time: 3 h

Procedure:
Combine (1-methyl-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (0.42 g, 1.4 mmol) and 48% hydrobromic acid (25 mL). Heat to reflux. After 3 hours, cool add water and a solution of potassium hydroxide (5 g) in water (50 mL). Extract twice with dichloromethane. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:34][C:35]1[O:36][CH:37]=[CH:38][N:39]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:34][C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: ClCc1ncco1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OCc3ncco3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8) and 2-(chloromethyl)oxazole by General Procedure N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:16].[CH3:17][NH:18][CH3:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][N:18]([CH3:19])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[F:16]
Reactant: O=CC1(c2ccc(Cl)c(F)c2)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2ccc(Cl)c(F)c2)CCCCC1
Yield: 97 %

Procedure:
The title compound was synthesized from 1-(4-chloro-3-fluorophenyl)cyclohexanecarbaldehyde and dimethyl amine using General Procedure H1 and was obtained in 97% yield. LCMS Rt=9.07 min, m/z=270 (M+1). 1H NMR (CDCl3, δ): 7.31 (t, J=8.2 Hz, 1H), 7.17 (dd, J=2.1, 11.7 Hz, 1H), 7.09 (dd, J=1.8, 8.5 Hz, 1H), 2.30 (s, 2H), 2.0 (m, 2H), 1.99 (s, 3H), 1.7-1.3 (m, 8H). 13C NMR (CDCl3, δ, mult): 159.2(0), 156.7(0), 147.8(0), 129.7(1), 123.9(1), 123.8(1), 117.5(0), 117.3(0), 115.9(1), 115.7(1), 72.5(2), 48.4(3), 43.3(0), 34.1(2), 26.4(2), 22.1(2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9](OCC)(=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.Cl>CCO>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc2ccccc2s1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of 2-aminothiophenol (10.7 mL, 0.1 mol) in diethyl oxalate (27.3 mL, 0.2 mol) is heated at reflux for 4 hr. The solution is cooled to rt and poured into a solution consisting of water (150 mL), conc. HCl (50 mL) and 95% EtOH (70 mL). With stirring, the oil dissolved and a solid formed. The solution is cooled in an ice bath, the solid is collected by vacuum filtration and the solids are washed with a solution consisting of EtOH/water (25/75) to afford a dark solid. This material is purified by crystallization from hot (68° C.) ligroin to yield ethyl 2-benzothiazolecarboxylate (7.5 g, 36%): Elemental analysis for C10H9NO2S: Calc: C, 57.95; H, 4.38; N, 6.76. Found: C, 57.99; H, 4.28; N, 6.78.
Reaction SMILES: O.[SH:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1.[Na].Br[CH2:11][Cl:12]>CC#N>[Cl:12][CH2:11][S:2][C:3]1[N:7]([CH3:8])[N:6]=[N:5][N:4]=1
Reactant: ClCBr
Reactant: Cn1nnnc1S
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: Cn1nnnc1SCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
A solution of sodium 5-mercapto-1-methyltetrazole hydrate (1.38 g, 10.0 mmol) in CH3CN (50 mL) was cooled in ice and treated in one portion with bromochloromethane (6.47 g, 50 mmol). The ice-bath was removed and the reaction mixture stirred at R.T. for 18 h. Then the solvent was evaporated and the crude product purified by chromatography on silica gel (eluted with CH2Cl2) to afford 1.27 g (77%) of the title compound, m.p.: 55°-57° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:16]([O:18][CH3:19])=[O:17])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:16]([OH:18])(=[O:17])[CH3:10].[NH2:8][C@@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)[C@@H]1CCCCC[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCCC[C@H]1N
Yield: 147.1 %

Procedure:
trans-Methyl 2-(dibenzylamino)cycloheptanecarboxylate (1.04 g, 2.94 mmol) was hydrogenated at 50 psi in 20 mL glacial acetic acid with 500 mg 10% palladium on carbon for 25 h. The reaction was filtered through celite and concentrated to yield trans-methyl 2-aminocycloheptanecarboxylate acetate (500 mg, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 3.71 (3H, s), 3.35-3.44 (1H, m), 2.59 (1H, td, J=8.62, 3.15 Hz), 1.84-1.96 (2H, m), 1.61-1.80 (4H, m), 1.41-1.60 (4H, m). MS [M+H]+=171.94.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 64.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 2,6-dichlorobenzoyl chloride (20 mg, 0.095 mmol), the title compound (20 mg, yield 64%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[NH:21][CH3:22])(=[O:3])[CH3:2].Cl.N.[CH2:25](O)[CH3:26]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:25][CH3:26])=[O:19])[CH:8]=[C:7]2[NH:21][CH3:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(NC)cc(C(=O)O)nc12
Reactant: CCO
Agent: Cl
Agent: N
Product: CCCc1c(O)c(C(C)=O)cc2c(NC)cc(C(=O)OCC)nc12

Procedure:
The crude product of step (d) (6.4 g) in ethanol (500 mls) which had been previously saturated with hydrogen chloride gas was heated under reflux for 1 hour. The reaction mixture was cooled, made basic with 880 ammonia and extracted with ethyl acetate, which was then washed with water and dried over magnesium sulphate. The solvent was removed by evaporation to leave 8.0 g of residual yellow solid. This solid was recrystallised from ethanol to give 3.8 g of yellow needles mp 219°-220°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][NH2:30]>C(Cl)Cl>[NH:29]([C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (120 g, 520 mmol) in DCM (250 mL) was added carbonyldiimidazole (96 g, 590 mmol) in portions at room temperature. After 30 minutes, the reaction mixture was added to a freshly prepared solution of hydrazine (27 g, 840 mmol) in DCM (100 mL). After 30 minutes, the reaction was washed with a saturated solution of sodium carbonate, brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was suspended in ether and filtered to give tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 4.15-4.10 (s, 2H), 3.95-3.90 (m, 2H), 2.80-2.60 (m, 2H), 2.25-2.20 (m, 1H), 1.62-1.55 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:34]=[CH:35][C:36]2[O:40][N:39]=[C:38]([OH:41])[C:37]=2[CH:42]=1.[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52]O)=[O:49])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[C:43]([O:47][C:48]([NH:50][CH2:51][CH2:52][O:41][C:38]1[C:37]2[CH:42]=[C:33]([F:32])[CH:34]=[CH:35][C:36]=2[O:40][N:39]=1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: Oc1noc2ccc(F)cc12
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1noc2ccc(F)cc12
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
To a solution of triphenylphosphine (0.87 g) in tetrahydrofuran (20 ml) was added diethyl azodicarboxylate (0.57 g) at 5° C. and the mixture was stirred at the same temperature for 15 minutes. Then 5-fluoro-3-hydroxy-1,2-benzisoxazole (0.46 g) was added and the mixture was stirred at the same temperature for 15 minutes followed by addition of N-t-butoxycarbonyl ethanolamine (0.48 g) and stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography with cyclohexane/ethyl acetate (9/1) as an eluent, to give the title compound (0.53 g, 60%) as a colorless powder.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53](C(O)=O)[CH2:54][OH:55])(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:29]([OH:31])=[O:30])=[O:13])[CH2:54][OH:55])(=[O:51])=[O:50])=[CH:45][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CO)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-L-serine (150 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 35 mg (46%) of the desired material.