Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([O:11][CH:12]([O:16][C:17]([NH:19][C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)=[O:18])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)C>[Pd].C(O)C>[CH3:14][CH:13]([CH3:15])[CH:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:16][C:17]([NH:19][C:20]1([C:23]([OH:25])=[O:24])[CH2:21][CH2:22]1)=[O:18]
Reactant: CC(C)C(OC(=O)/C=C/c1ccccc1)OC(=O)NC1(C(=O)O)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)C(OC(=O)CCc1ccccc1)OC(=O)NC1(C(=O)O)CC1

Procedure:
A dry 100 mL round-bottomed flask equipped with a magnetic stir bar and a rubber septum was charged with 1-{[1-((2E)-3-phenylprop-2-enoyloxy)-2-methylpropoxy]carbonylamino}cyclopropanecarboxylic acid (18) (0.62 g, 1.8 mmols) and 10% palladium on carbon in a 1: I mixture of ethylacetate and ethanol. The reaction was done at 1 atm pressure under a hydrogen balloon at ca. room temperature. After the reaction was complete, the solution was filtered through Celite and the solvents removed in vacuo using a rotary evaporator. The dry, crude residue was dissolved in a small amount of a mixture of 60% (v/v) acetonitrile/water (ca. 10 mL), and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative HPLC. After lyophilization of the solvents, the title compound (19) was obtained as a yellow semisolid (70% yield). 1H NMR (CDCl3, 400 MHz): δ=7.33 (t, 2H), 7.20 (m, 3H), 6.61 (d, 1H), 6.05 (s, 0.35H), 5.35 (s, 0.65H), 2.98 (t, 2H), 2.71 (m, 2H), 2.01 (m, 1H), 1.65 (m, 2H), 1.36 (m, 2H), 0.98 (d, 6H). MS (ESI) m/z 371.92 (M+Na)+; 348.01 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:11]=2)[N:6]([CH2:21][C:22]([O:24]C)=[O:23])[N:5]=1)(=[O:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[N:16]=[CH:17][CH:18]=[CH:19][N:20]=3)[CH:11]=2)[N:6]([CH2:21][C:22]([OH:24])=[O:23])[N:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nn(CC(=O)O)c2ccc(OCc3ncccn3)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To methyl 2-(3-acetyl-5-(pyrimidin-2-ylmethoxy)-1H-indazol-1-yl)acetate (1.93 g, 5.67 mmol) in THF (15 mL) and water (15 mL) was added LiOH.H2O (0.25 g, 5.95 mmol). The reaction mixture was stirred at RT for 1.5 h. Volatiles were evaporated and the residue was freeze-dried overnight to give the title compound. MS (LC/MS): 327.0 [M+H]+, 325.1 [M+H]+; tR (HPLC conditions c): 3.24 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[CH:11][CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH:18]=[CH:17][CH2:16][CH2:15]1>>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH2:19]2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH2:12][CH3:13]
Reactant: CCC=CCOc1cc(Cl)ncn1
Reactant: C1=CCNCC1
Product: CCC#CCOc1cc(N2C=CC=CC2)ncn1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
0.3 g of 4-chloro-6-(2-pentenyloxy)pyrimidine and 0.25 g of 1,2,3,6-tetrahydropyridine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.23 g of 1-(4-(2-pentynyloxy)pyrimidin-6-yl)pyridine (hereinafter, referred to as Compound (55)).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:3]1=[O:16].[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[CH:27]=[O:28]>>[CH:13]1([CH2:12][N:4]2[C:5]3[S:11][C:10]([CH:27]([OH:28])[C:19]4[N:18]([CH3:17])[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=4)=[CH:9][C:6]=3[C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:16])[CH2:14][CH2:15]1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: Cn1c(=O)c2ccsc2n(CC2CC2)c1=O
Product: Cn1c(=O)c2cc(C(O)c3nc4ccccc4n3C)sc2n(CC2CC2)c1=O

Procedure:
The title compound was prepared from 3-Methyl-1-(cyclopropylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 32 step a) and 1-methylbenzimidazole-2-carboxaldehyde following the method of Example 1 step d.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:32])[N:21]([CH3:31])[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:31][N:21]([CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:20](=[O:32])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (1.43 g, 3.10 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. The solution was stirred at 0° C. for 90 min. Dichloromethane (35 ml) and saturated sodium hydrogen carbonate solution were added. Solid sodium hydrogen carbonate was added until pH 7. The phases were separated. The aqueous phase was extracted with dichloromethane (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 0.91 g of crude (2R)-N-methyl-2-methylamino-3-(2-naphthyl)-N-(3-phenylpropyl)propionamide, which was used without further purification.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:25]([Br:26])=[CH:24][CH:23]=[CH:22][C:15]=1[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17]>C(Cl)Cl>[Br:26][C:25]1[CH:24]=[CH:23][CH:22]=[C:15]2[C:14]=1[NH:13][C:2](=[O:4])[N:18]([CH:19]1[CH2:20][CH2:21]1)[C:16]2=[O:17]
Reactant: Nc1c(Br)cccc1C(=O)NC1CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CC1
Reaction time: 17 h
Yield: 249.8 %

Procedure:
Triphosgene (Sigma-Aldrich; 2.79 g, 9.41 mmol) was added to a solution of 2-amino-3-bromo-N-cyclopropylbenzamide (723a; 6.00 g, 23.52 mmol) in DCM (235 mL) at RT. The mixture was heated to reflux and stirred overnight (17 h). The mixture turned cloudy upon heating. The next morning the reaction mixture was cooled and concentrated to afford 8-bromo-3-cyclopropylquinazoline-2,4(1H,3H)-dione (723b; 6.61 g, 23.51 mmol, 100% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (d, J=8.02 Hz, 1H), 8.06 (br. s., 1H), 7.78 (dd, J=7.82, 1.17 Hz, 1H), 7.10 (t, J=7.92 Hz, 1H), 2.74-2.84 (m, 1H), 1.21 (q, J=7.04 Hz, 2H), 0.83-0.91 (m, 2H). m/z (ES, +ve) 281.0, 283.0 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:25][CH:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: COCOc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.94 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 0.8 g of 4-methoxymethoxybenzyl chloride, and then 0.55 g of anhydrous sodium carbonate was added thereto. The mixture was stirred overnight at room temperature. Then, procedures similar to those in Preparation Example 3 were carried out to obtain 520 mg of the aimed compound, m.p. 50.0°~54.0° C.
Reaction SMILES: [I-].[Cl:2][C:3]1[C:4]([CH2:12][CH:13]([C:19]([O:21][CH3:22])=[O:20])[CH2:14][N+](C)(C)C)=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1>O>[Cl:2][C:3]1[C:4]([CH2:12][C:13](=[CH2:14])[C:19]([O:21][CH3:22])=[O:20])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1
Reactant: COC(=O)C(Cc1cc2c(cc1Cl)OCO2)C[N+](C)(C)C
Agent: [I-]
Solvent: O
Product: C=C(Cc1cc2c(cc1Cl)OCO2)C(=O)OC
Yield: 87.4 %

Procedure:
The operation is carried out as in Stage 3 of Example 1 starting with 484 mg of the product obtained in Stage 3 above, 5 ml of water and 2 ml of 2N soda. In this way 244 mg of expected product (white powder) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=3[Cl:18])[NH2:14])=[N:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:14][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:15]=[CH:16][C:17]=3[Cl:18])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (I-2b) (1 g, 3.08 mmol, 1.00 equiv) in DMF (10 mL) at 0° C. was added 0.5 ml of pyridine followed by isopropyl chloroformate (solution 1M in toluene) (3.85 ml, 3.85 mmol, 1.25 equiv). The reaction mixture was stirred overnight at room temperature and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography (0 to 100% Ethyl acetate/Hexanes) to afford the title compound I-11. 1H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=8.8, 1H), 4.97 4.80 (m, 1H), 1.26 (d, J=6.2, 6H); MS M/Z=409.0 (M+1). RT=1.77: Method B.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[N:6]2[N:5]=1)=O.[F:21][C:22]([F:34])([F:33])[C:23]1[NH:24][C:25]2[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:26]=2[N:27]=1>>[CH3:20][O:19][C:16]1[N:15]=[CH:14][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:32][C:30]4[CH:29]=[CH:28][C:26]5[N:27]=[C:23]([C:22]([F:34])([F:33])[F:21])[NH:24][C:25]=5[CH:31]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2nc(C(F)(F)F)[nH]c2c1
Reactant: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc5nc(C(F)(F)F)[nH]c5c4)nn23)cn1

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine (60 mg, 0.2 mmol) was coupled to 2-trifluoromethyl-3H-benzimidazol-5-ylamine (72 mg, 0.36 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 32 mg (30%) of tan powder; LC/MS: 426 (M+H); HPLC: 97% pure, RT=3.06 min; 1H NMR: (DMSO, δ) 9.64 (s, 1H), 9.02 (s, 1H), 8.97 (d, J=2.0, 1H), 8.56 (dd, J=8.8, 2.5, 1H), 8.12 (s, 1H), 7.66 (m, 2H), 7.22 (d, J=4.9, 1H), 7.01 (d, J=8.8, 1H), 6.99 (d, J=4.9, 1H), 3.94 (s, 3H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]3)=[CH:17][C:15]=2[N:16]=1>COCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCCCC2)nc2cc3c(cc21)CCC3
Yield: 92.7 %

Procedure:
2-(1-Piperidinyl)ethylamine (0.67 mL, 4.7 mmol) was added to a stirred solution of chloride 21 (348 mg, 1.6 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 36 (465 mg, 95%) as a yellow solid: mp (MeOH/EtOAc) 151-153° C.; 1H NMR δ 8.06 (s, 1H, H-9), 7.39 (s, 1H, H-5), 5.91 (br s, 1H, NH), 3.52-3.57 (m, 2H, CH2N), 2.97-3.03 (m, 4H, H-6, H-8), 2.58 (t, J=6.0 Hz, 2H, CH2N), 2.40-2.47 (m, 4H, 2×CH2N), 2.10-2.18 (m, 2H, H-7), 1.55-1.63 (m, 4H, 2×CH2), 1.42-1.48 (m, 2H, CH2); 13C NMR δ 158.7, 154.5, 148.8, 143.1, 129.7, 120.5, 114.6, 57.0, 54.3 (2), 37.9, 33.1, 32.3, 25.9 (2), 25.7, 24.4. Anal. calcd for C17H23N5O.¼H2O: C, 64.2; H, 7.5; N, 22.0. Found: C, 64.6; H, 6.9; N, 22.1%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br.Br[CH2:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]([C:13]2[O:10][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=3[CH:7]=2)=[O:15])[CH:17]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1cccnc1)c1cc2cc(Br)ccc2o1
Reaction time: 5 h
Yield: 72.2 %

Procedure:
A mixture of 5-bromosalicylaldehyde (17.7 g), 3-bromoacetylpyridine hydrobromide (25.3 g) and anhydrous potassium carbonate (60.8 g), in 2-butanone (200 ml) was heated under reflux with stirring for 5 hours. The mixture was filtered and the solid was washed with 2-butanone. The combined filtrate and washings were evaporated and the residue was crystallised from methanol to give 5-bromobenzofuran-2-yl pyrid-3-yl ketone (19.2 g), m.p. 144°-145°.
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OCCC1C=C[C:37]([C:38]#[N:39])=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[NH2:39][CH2:38][CH2:37][C:9]1[CH:10]=[CH:2][C:3]([C:4]#[N:5])=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCN)cc1
Reaction time: 1 h

Procedure:
A mixture of phthalimide (20.0 g) and triphenylphosphine (35.65 g) was added dropwise to a mixture of 4-(2-hydroxyethyl)benzonitrile (20.0 g) and diethylazodicarboxylate (21.4 ml) in THF (650 ml) with stirring over one hour. The mixture was stirred at ambient temperature for 4 days. The solvent was removed under reduced pressure. Methanol (500 ml) and hydrazine hydrate (13 ml) were added to the residue and the mixture was boiled under reflux with stirring for 5 hours. The solvent was removed under reduced pressure and aqueous acetic acid (420 ml of glacial acetic acid in 1030 ml of water) was added to the residue. This mixture was stirred for 1 hour and then filtered. The filtrate was added to ice and basified with solid potassium hydroxide. The mixture was extracted with dichloromethane to give an oil which was purified by flash column chromatography to give 4-(2-aminoethyl)benzonitrile, as an oil. A sample was dissolved in ethereal hydrogen chloride to give the hydrochloride salt, m.p. 211-213° C.
Reaction SMILES: [C:1]1([C:11]([NH:13][NH2:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(O)(O)(=O)=O.C[NH:21][C:22](=[NH:24])S.[OH-].[Na+].O>CO>[C:22]([NH:14][NH:13][C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:12])(=[NH:21])[NH2:24]
Reactant: CNC(=N)S
Reactant: NNC(=O)c1cccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N=C(N)NNC(=O)c1cccc2ccccc12

Procedure:
The synthesis method of Example 1-(1) was applied. The compound (18.3 g) obtained in (2) above, methylisothiourea sulfate (81.6 g), sodium hydroxide (11.7 g), water (90 ml) and methanol (180 ml) were used as reagents and the mixture was reacted at 60° C. for 48 hours to give 39.7 g of a yellow solid. A portion (21.2 g) from the obtained solid was used in the next reaction.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([OH:59])[CH2:40]2)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][CH:41]([OH:59])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(O)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 88.7 %

Procedure:
To a solution of 41 (20 mg, 25 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) was added Pd(OH)2 on carbon (15 mg). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory HPLC to give 44 (10 mg, 90%) as a mixture of two diastereomers. LCMS m/z 433 (M−OH).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[N:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:17]=1[CH2:18][C:19](Cl)=[O:20]>>[CH2:8]([N:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH:2]([NH:1][C:19]([CH2:18][C:17]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]=1)=[O:20])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Reactant: CCN(CC)CCC(N)c1ccccc1
Product: CCN(CC)CCC(NC(=O)Cc1ccc2ccccc2n1)c1ccccc1
Yield: 95.9 %

Procedure:
The procedure of Example 1 was repeated using 618 mg (3.0 mmol.) of N-(3-amino-3-phenylpropyl)-N,N-diethylamine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.08 g (yield: 100%) of the subject compound as a pale yellow oily product.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([C:15]2[NH:19][N:18]=[N:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na]>COCCO>[CH2:1]([N:19]1[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:16][N:17]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: COCCO
Product: c1ccc(Cn2nnnc2-c2ccccc2)cc1
Yield: 92.5 %

Procedure:
Benzyl chloride (0.15 mole; 19.0 g), sodium 5-phenyltetrazole (0.165 mole; 27.4 g) and 2-methoxyethanol (100 ml) were heated at 100° C. for 3.5 hours). The mixture was cooled to precipitate NaCl. Water (250 ml) was added to the filtrate to precipitate a product which was filtered, washed with H2O (50 ml) and dried in-vacuo at 60° C. for four hours. The product weight was 32.8 g. (92.5 percent yield), m.p. 54°-67° C. Reported; 2-benzyl-5-phenyltetrazole, m.p. 65.5°-66° C. 1-benzyl-5-phenyltetrazole, m.p. 92.5°-93° C. Elemental analysis found: C, 71.57; H, 5.30; N, 21.39. Calculation for C14H 12N4 : C, 71.17; H, 5.12; N, 23.71. 13C NMR established a 3/1 isomer ratio for the 2-benzyl/1 -benzyl substitution products, respectively. The isomers are represented by the following structures; ##STR6##
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2([CH2:36][O:37][CH3:38])[CH2:35][O:34][CH2:33]2)=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC(F)F)COC1
Temperature: 70 °C
Yield: 18.4 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (138 mg, 0.75 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (97.5 mg, 0.5 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 18%).
Reaction SMILES: [H-].[Na+].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][N:20]=1)=[O:18])(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C.O>[CH2:27]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([OH:16])=[O:18])=[N:20][CH:21]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCBr
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)O)nc1
Temperature: 90 °C

Procedure:
Sodium hydride (50% in oil, 250 mg) was added to 5-hydroxypyridine-2-carboxylic acid benzhydryl ester (2.0 g) dissolved in DMF (20 ml) and, after gas evolution ceased, 1-bromobutane (0.72 g) was added. The mixture was heated at 90° C. for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrogenated in analogy to method B. The product with the molecular weight of 195.22 (C10H13NO3); MS (ESI): 196 (M+H+) was obtained in this way.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH:7]2[O:11][C:10](=[O:12])[N:9]=[N:8]2)[CH2:6][CH2:5]1.[Cl:13][C:14]1[CH:15]=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:17]=[C:18]([Cl:21])[C:19]=1Cl.O>CN(C)C=O>[CH3:3][C:4]1([C:7]2[O:11][C:10](=[O:12])[N:9]([C:19]3[C:18]([Cl:21])=[CH:17][C:16]([C:22]([F:23])([F:25])[F:24])=[CH:15][C:14]=3[Cl:13])[N:8]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: CC1(C2N=NC(=O)O2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c(=O)o2)CC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 9.9 %

Procedure:
After 44 mg (1.1 mmol) of 60% sodium hydride was added to a solution of 0.14 g (1 mmol) of 5-(1-methylcyclopropyl)-1,3,4-oxadiazolin-2-one in 5 ml of N,N-dimethylformamide at room temperature, the mixture was stirred at the same temperature for 15 minutes. To the mixture was added 0.25 g (1 mmol) of 3,4,5-trichlorobenzotrifluoride followed by heating a 80° C. for 6 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated under reduced pressure to give the crude product. The crude product was subjected to silica gel column chromatography to give 35 mg of 5-(1-methylcyclopropyl)-3-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazoline-2-one.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26].[OH-].[Na+]>ClCCl.CN(C)C=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17](=[O:19])[N:23]1[CH2:24][CH2:25][NH:20][C:21](=[O:26])[CH2:22]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCNC(=O)C1

Procedure:
BOC-L-Phenylalanine (530 mg, 2 mmol) and piperazin-2-one (J. Am. Chem. Soc. 62 1202 (1940), 200 mg, 2 mmol) were coupled according to procedure A (2:1 dichloromethane/dimethylformamide reaction solvent, washed with 1 N NaOH after acid washes) and the product used without further purification. Yield 404 mg, 58%.