Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Cl:10][C:11]1[C:12]([CH3:16])=[N:13][NH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>CCOC(C)=O.[Cl-].[NH4+].[OH-].[NH4+].[Cu]I.C1(C)C=CC=CC=1>[Cl:10][C:11]1[C:12]([CH3:16])=[N:13][N:14]([C:2]2[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=2[NH2:4])[CH:15]=1
Reactant: Cc1cccc(Br)c1N
Reactant: Cc1n[nH]cc1Cl
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(-n2cc(Cl)c(C)n2)c1N
Temperature: 110 °C
Reaction time: 18 h

Procedure:
2-Bromo-6-methylaniline (1.080 mL, 8.58 mmol), 4-chloro-3-methyl-1H-pyrazole (1.0 g, 8.58 mmol), potassium carbonate (2.49 g, 18.02 mmol), and copper(I) iodide (0.082 g, 0.429 mmol) were added to a RBF which was evacuated and flushed with N2 3×. Toluene (9 mL) (degassed by bubbling N2 through solution for 10 minutes) and N1,N2-dimethylethane-1,2-diamine (0.185 mL, 1.716 mmol) were added and the mixture was heated in an oil bath at 110° C. After 18 h, the reaction was allowed to cool, diluted with EtOAc, and 10:1 saturated ammonium chloride/ammonium hydroxide. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with 1:2 EtOAc in hexanes to provide 2-(4-chloro-3-methyl-1H-pyrazol-1-yl)-6-methylaniline.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[C:34]1([CH2:40][CH2:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O>[C:34]1([CH2:40][CH2:41][NH:42][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: NCCc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(CCNc2cccc3ccccc23)cc1
Yield: 97 %

Procedure:
288 parts of β-naphthol, 9 parts of triphenyl phosphite and 270 parts of 2-phenylethylamine are heated to 180° C whilst stirring. The elimination of water commences at this temperature and has ended after 5 hours at an internal temperature of 240° C. 36 parts of water are collected in the water separator. After distilling off excess β-naphthol and amine under reduced pressure, 2-phenylethyl-naphthylamine distils, at a boiling point of 230° - 231° C/5 mm Hg. 479 parts of 2-phenylethyl-naphthylamine are obtained, corresponding to a yield of 97% of theory.
Reaction SMILES: [F:1][C:2]([F:41])([C:37]([F:40])([F:39])[F:38])[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]([OH:15])=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.P(CCC(O)=O)(CCC(O)=O)CCC(O)=O.Cl>ClCCl>[F:41][C:2]([F:1])([C:37]([F:38])([F:39])[F:40])[C@@H:3]([NH:11][C@@H:12]([CH2:16][SH:17])[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H](CS)N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of 2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-3-tritylsulfanylpropionic acid (6.92 g, 12 mmol) in dichloromethane (10 mL), triethylsilane (3.73 mL, 23.4 mmol) and TFA (3.61 mL, 46.9 mmol) were added at room temperature. The reaction mixture was stirred for 4 h. The solvent and volatiles were evaporated on rotovap, benzene was added to the residue and the mixture was evaporated again to ensure complete removal of excess TFA. The residue was dissolved in 1 N NaOH (50 mL) and extracted with hexanes. To the resulting solution, P(CH2CH2CO2H)3.HCl (0.343 g, 1.2 mmol) was added, and a 0.2 M stock solution of 2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-3-mercaptopropionic acid was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[NH:15][N:14]=[N:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].C[Si](C)(C)CCOC[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C>[OH:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:13]2[C:8]3[N:9]=[C:10]([NH2:12])[N:11]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:7]=3[N:15]=[N:14]2)=[CH:27][CH:26]=1
Reactant: Nc1nc(-c2ccco2)c2[nH]nnc2n1
Reactant: C[Si](C)(C)CCOCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccco2)c2nnn(Cc3ccc(O)cc3)c2n1
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
A solution of 7-(2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (400 mg, 1.98 mmol) in DMF (3 mL), at 0° C., was treated with 60% sodium hydride in mineral oil (80 mg, 1.98 mmol), stirred for 30 min, treated with 4-(2-(trimethylsilyl)ethoxymethoxy)benzyl bromide (1.23 g, 3.96 mmol), stirred at room temperature for 48 h and purified by chromatography [SiO2; EtOAc:heptane, (1:2)]. The resulting yellow solid was dissolved in MeOH:DMF (1:2), passed through an ion exchange cartridge (Isolute SPE SCX-2), concentrated in vacuo, and washed with water and ether to give the title compound (41 mg, 7%) as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.CCCCC.CON(C)[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]>CCOCC>[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29]
Reactant: CON(C)C(=O)C1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Nc1ccccc1C(=O)C1CCCC1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To a stirred solution of phenyl-carbamic acid tert-butyl ester (1.2 g, 6.2 mmol) in Et2O (12 mL) under a nitrogen atmosphere was added dropwise a 1.7 M solution of t-BuLi in pentan (8.4 mL, 14.3 mmol) over a 10-min period at −20° C. The mixture was stirred at −10° C. for 2.5 h and then cyclopentanecarboxylic acid methoxy-methyl-amide (1.07 g, 6.8 mmol) was added over 5 min. The mixture was allowed to warm to room temperature and stirred for further 1 h before it was quenched with aqueous NH4Cl. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo. The crude material was dissolved CH2Cl2 (18 mL) and TFA (6 mL) and stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo, and added aqueous NaHCO3 to pH 7 and extracted with CH2Cl2. The combined organic phases were dried and concentrated in vacuo to give 1.03 g (68%) of (2-amino-phenyl)-cyclopentyl-methanone as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:22]([N:16]1[CH2:17][CH:6]2[CH:7]([C:2]([CH3:9])([CH3:1])[CH:3]=[CH:4][C:5]2=[O:8])[CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)C=CC(=O)C=C1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C=CC(=O)C2CN(Cc3ccccc3)CC21

Procedure:
To a solution of 15.96 g of 4,4-dimethyl-2,5-cyclohexadienone and 46 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 200 cm3 of dichloromethane are added, at a temperature of 10° C., 8 drops of trifluoroacetic acid. The reaction mixture is brought to reflux for 2 hours and potassium carbonate is then added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 8.5 cm, height 30 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 100 cm3 fractions. Fractions 38 to 56 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 14.7 g of (3aRS,7aRS)-2-benzyl-7,7-dimethyl-2,3,3a, 4,7,7a-hexahydro-1H-4-isoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]=[CH:7][N:8]([C@H]3[C@@H](O)[C@@H](O)[C@H](CO)O3)[C:9]=2[N:10]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=1.Cl>CS(C)=O>[NH2:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Agent: Cl
Solvent: CS(C)=O
Product: Nc1nc2ncn(Cc3ccc(Cl)cc3)c2c(=O)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 2-amino-9-((2R,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (14 g, 49.47 mmol) in DMSO (50 mL) was added 1-chloro-4-(chloromethyl)benzene (10 g, 62.16 mmol). The reaction was stirred at 50° C. overnight. The mixture was cooled to room temperature and HCl (50 mL, 10% w.w) was added. The reaction was stirred at 70° C. for 2 h. The reaction was cooled and the precipitate was collected and washed with water and ethanol. The product was dried under vacuum to give 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (10 g, 74.1% yield) as grey solid. LCMS retention time 0.529 min; LCMS MH+ 276.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1)=[O:4].CCCCCC.CC[O:23]C(C)=O>CC(C)=O.S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:23])=[O:14])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(CCCCO)s1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3 (1.14 g, 5.3 mmol) in acetone (15 mL) was added dropwise to a cold solution (ice bath) of CrO3 (3 g, 30 mmol) in sulfuric acid (23 mL) and water (67 mL). After the addition, the resulting solution was stirred in an ice bath for an additional 2 h and the solution was allowed to warm to room temperature overnight. TLC indicated the disappearance of the starting alcohol and the formation of one major spot at Rf=0.35 (hexane/EtOAc 2:1). The solution was extracted with 5×30 mL of ethyl ether and dried over Na2SO4. After evaporation of the solvent under reduced pressure, the resulting residue was flash chromatographed through silica gel column (3.5×15 cm) using hexane/EtOAc (2:1) as eluent. The desired fraction (TLC) was collected and the solvent was evaporated under reduced pressure to afford 570 mg of 4 as colorless oil. 1H NMR (DMSO-d6): δ 1.79-1.87 (m, 2H), 2.24-2.27 (t, J=7.2 Hz, 2H), 2.82-2.86 (t, J=7.2 Hz, 2H), 3.77 (s, 3H), 6.95-6.96 (d, J=3.6 Hz, 1H), 7.63-7.64 (d, J=3.6 Hz, 1H), 12.17 (br, 1H). HRMS calcd for C10H12O4S (M+), 228.0456; found: 228.0458.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][C:20]([NH:23][C:24]([CH2:26][O:27]C(=O)C)=[O:25])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([NH:23][C:24](=[O:25])[CH2:26][OH:27])=[CH:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH3:38])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cc(NC(=O)CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
To a solution of 30 mg (0.05 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-ylcarbamoyl)-methyl ester in 2 ml tetrahydrofuran were added 2 ml 1 N sodium hydroxide solution at room temperature. After stirring for 15 min, ethyl acetate was added, the aqueous phase was separated and the organic layer was dried (sodium sulfate). After evaporation the residue was purified by flash-chromatography to give 15 mg (54%) of the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2[CH3:20])[CH2:4][O:3]1.[CH2:22](C1C=C(C=C(C)C=1O)C#N)C.CC1(C)O[C@@H](CO)CO1>>[CH3:1][C:2]1([CH3:21])[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]([CH3:20])=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:17][C:18]=2[CH2:19][CH3:22])[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: CCc1cc(C#N)cc(C)c1O
Agent: CC1(C)OC[C@H](CO)O1
Product: CCc1cc(C(=N)NO)cc(C)c1OC[C@H]1COC(C)(C)O1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-N-hydroxy-3,5-dimethyl-benzamidine from 3-ethyl-4-hydroxy-5-methyl-benzonitrile and (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol; LC-MS*: tR=0.97 min.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([C:13]([F:16])([F:15])[F:14])[N:5]=1)[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([C:13]([F:14])([F:15])[F:16])=[CH:7][CH:8]=1
Reactant: CCNc1nc(C(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNc1nc(C(F)(F)F)ccc1N
Yield: 99.5 %

Procedure:
A solution of 2-(ethylamino)-3-nitro-6-(trifluoromethyl)pyridine (1.1 g, 4.9 mmol) in MeOH (40 mL) was stirred overnight at room temperature under hydrogen (1 atm.) in the presence of 20% Pd(OH)2/C (100 mg). The catalyst was removed by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure to give the title compound as an orange oil (1 g).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([NH:26][NH:27][C:28](=O)[CH2:29][N:30]1[C:34]([CH2:35][CH3:36])=[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[C:32]([CH2:46][CH3:47])=[N:31]1)(=O)[CH3:24]>O1CCCC1>[CH2:46]([C:32]1[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)=[C:34]([CH2:35][CH3:36])[N:30]([CH2:29][C:28]2[S:10][C:23]([CH3:24])=[N:26][N:27]=2)[N:31]=1)[CH3:47]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1nn(CC(=O)NNC(C)=O)c(CC)c1Oc1ccc(C#N)cc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2nnc(C)s2)c(CC)c1Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
Lawesson's reagent (213 mg, 0.53 mmol) was added to a solution of the acetyl acetohydrazide of step (b) of Example 140 (170 mg, 0.48 mmol) in tetrahydrofuran (10 ml) and the reaction mixture was stirred at room temperature for 18 hours. It was then evaporated to dryness and purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (1:1 then 2:1, by volume) to provide the title compound (80 mg, 47%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:21])[CH2:6][C:7]1[N:11]([CH:12]2[CH2:14][CH2:13]2)[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1)C.O.[NH2:24][NH2:25]>C(O)C>[CH:12]1([N:11]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:9][N:8]=[C:7]2[CH2:6][CH:5]([CH3:21])[C:4]([NH:24][NH2:25])=[O:3])[CH2:14][CH2:13]1
Reactant: NN
Reactant: CCOC(=O)C(C)Cc1nnc(-c2ccncc2)n1C1CC1
Solvent: CCO
Solvent: O
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)C(=O)NN

Procedure:
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid ethyl ester (2.14 g, 7.1 mmol) was mixed with hydrazine monohydrate in ethanol at 120° C. in a sealed flask for 2 hours. The reaction mixture was concentrated and triturated with ether to give 3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid hydrazide. This compound was mixed with 3-Chloro-benzimidic acid ethyl ester hydrochloride (0.722 g, 7.8 mmol) in ethanol at 130° C. o.n. The reaction mixture was concentrated, quenched with saturated sodium carbonate, extracted with DCM. The organic layer was dried and purified by column chromatograph with 5% methanol (2M NH3) in DCM to racemic 4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H[1,2,4] triazol-3-yl)-pyridine 1.19 g (41.1%). This material (70 mg) was separated on Chiralpak AD using ethanol as eluent to give the title compound. 1H-NMR: 8.77(d, 2H), 8.02 (s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.51 (d, 1H), 7.47(t, 1H), 4.12 (m, 1H), 3.69 (dd, 1H), 3.44 (m, 1H), 3.26 (dd, 1H), 1.66 (d, 3H), 1.24 (m, 2H) and 0.79 (m, 2H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9](C)([O-])[CH3:10].[K+].C(Br)C=C.O>O1CCCC1>[CH:1]1([O:7][CH2:10][CH:9]=[CH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: OC1CCCCC1
Agent: CC(C)(C)O[K]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCOC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 870 g of tetrahydrofuran were dissolved 200 g (2 mol) of cyclohexanol and 224 g (2 mol) of potassium t-butoxide. With stirring at room temperature, 242 g (2 mol) of allyl bromide was added dropwise so that the temperature might not exceed 60° C. At the end of addition, the solution was heated at 60° C. on an oil bath and ripened for one hour at the temperature. The solution was allowed to cool down to room temperature, and 11.2 g (0.1 mol) of t-butoxypotassium was added. With stirring at room temperature, 12.1 g (0.1 mol) of allyl bromide was added dropwise. The solution was heated at 60° C. on an oil bath and ripened for one hour at the temperature. The solution was cooled in an ice bath, and 550 g of water was added. The organic layer was collected. The solvent was distilled off in vacuum, yielding 280 g of a crude end product. The product was used in the subsequent reaction without further purification.
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.[C:25]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])([CH3:28])([CH3:27])[CH3:26].CC1C(C)=CC=CC=1C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1OC)=O>>[C:25]([C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([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:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Agent: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C
Product: CC(C)(C)c1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 44.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2-tert-butylbenzoyl chloride (0.143 mmol), the title compound (20 mg, yield 44%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[C@@H:18]([CH2:24][NH:25][C:26]3[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=3)[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:21][CH2:20][C@H:19]3[C@@H:18]([CH2:24][N:25]([C:26]4[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=4)[CH:22]3[OH:23])[C@@H:17]2[C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CNC2=CC(=O)CC2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H](O[C@H]1CC[C@@H]2C(O)N(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a solution of the intermediate from Step O (20 mg, 0.0348 mmol) in 5 mL dichloromethane was added Dess-Martin periodinane (16 mg, 0.038 mmol) at room temperature. The mixture was stirred at room temperature for 0.5 hr. The solvent was removed under vacuum and the residue was purified by preparative TLC (9.5:5 dichloromethane: 2N NH3 in methanol) to give 8 mg of the title compound. 1H-NMR (CDCl3) δ: 7.71 (1H, s), 7.22 (2H, s), 7.03 (2H, m), 6.90 (2H, m), 5.30, 5.20 (1H, two doublets), 5.28 (1H, two singlets), 4.45 (1H, m), 3.35 (1H, m), 3.20 (1H, m), 3.00 (1H, m), 2.84 (1H, m), 2.55-2.30 (6H, m), 2.03 (1H, m), 1.80-1.85 (4H, m), 1.33 (3H, d, J=6.5 Hz). MS: (MH)+ 572.5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[NH2:30][C:31]1[N:32]=[CH:33][C:34]([C:41]2[CH:51]=[CH:50][C:44]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])=[CH:43][CH:42]=2)=[N:35][C:36]=1[C:37]([NH:39][NH2:40])=[O:38].[CH3:52][O:53][C:54]1[CH:58]=[CH:57][S:56][C:55]=1[C:59](O)=[O:60]>C(Cl)Cl.O>[NH2:30][C:31]1[N:32]=[CH:33][C:34]([C:41]2[CH:42]=[CH:43][C:44]([C:45]([N:47]([CH3:48])[CH3:49])=[O:46])=[CH:50][CH:51]=2)=[N:35][C:36]=1[C:37](=[O:38])[NH:39][NH:40][C:59]([C:55]1[S:56][CH:57]=[CH:58][C:54]=1[O:53][CH3:52])=[O:60]
Reactant: COc1ccsc1C(=O)O
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccsc1C(=O)NNC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TBTU (160.4 mg, 0.4995 mmol) and Et3N (33.70 mg, 46.42 μL, 0.3330 mmol) were added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) and 3-methoxythiophene-2-carboxylic acid (52.67 mg, 0.3330 mmol) in CH2Cl2 (2.000 mL) and the resulting solution stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (3×5 mL), and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo to leave 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide as a yellow oil. POCl3 (1.788 g, 1.087 mL, 11.66 mmol) was added to 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide and the resulting mixture heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and ice/water added carefully with vigourous stirring between additions. The mixture was left to stir at room temperature for 20 min and then diluted with dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and combined organics dried over MgSO4 and concentrated in vacuo. Solid obtained is re-dissolved in CH2Cl2 and purified by column chromatography on the ISCO column companion system (12 g column, 0-5% MeOH/ CH2Cl2). Product fractions were combined and concentrated in vacuo. This was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (33.0 mg, 23% yield) 1H NMR (400 MHz, DMSO) d 2.98 (s, 3H), 3.01 (s, 3H), 4.07 (s, 3H), 7.30 (d, 1H), 7.56 (d, 2H), 7.70 (br s, 2H), 7.96 (d, 1H), 8.14 (d, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 423.19