Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[N:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].COC=COC>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:32]3[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:12]=2)[N:3]=1
Reactant: N#Cc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Reactant: OB(O)c1cccnc1F
Agent: COC=COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)cc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl]benzonitrile (0.086 g, 0.22 mmol) (Example 50), (2-fluoropyridin-3-yl)boronic acid (0.047 g, 0.33 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.018 g, 0.022 mmol), potassium carbonate (0.091 g, 0.66 mmol) and solvent (3 mL of a mixture of dimethoxyethene, water and ethanol in a ratio of 6:3:1) was irradiated under argon atmosphere in a microwave at 125° C. for 6 min. When cooled to ambient temperature the mixture was partitioned between ethyl acetate and water; the organic phase was dried over magnesium sulfate and evaporated. Purification by preparative HPLC to give 0.062 g (70% yield) of the title compound. 1H NMR (DMSO-d6) δ 8.22 (dd, J=3.28, 1.52 Hz, 1 H), 8.05-7.94 (m, 1 H), 7.84-7.75 (m, 2 H), 7.75-7.69 (m, 2 H), 7.56-7.34 (m, 9 H), 6.90 (br s, 2 H); MS (AP) m/z 405 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[Na].O.C(O)(=O)C.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)nc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Amino-4-chloro-6-methyl-5-nitropyrimidine (Boon et al., J. Chem. Soc., 96-102 (1951)) (1.24 g, 6.58 mmol) was added to a solution of sodium (0.21 g, 9.13 mmol) in benzyl alcohol (14 mL) under argon. The solution was heated in a 135° C. oil bath for 3.5 h, and was poured into water (70 mL) with constant stirring for 10 min. After neutralization with glacial acetic acid, a yellow precipitate formed which was collected by filtration and washed with water. This solid was crystallized from benzene to give 5b as a bright yellow crystalline solid: yield, 0.57 g (33%); mp 159°-160° C.; UV (pH 1) λmax 268 nm (ε=0.783×104), 345 (sh) (0.104×104); (pH 6.9) 282 (0.564×104), 345 (sh) (0.338×104); (pH 13) 282 (0.549×104), 345 (sh) (0.332×104); 1H NMR δ2.35 (s, 3H, CH3), 5.44 (s, 2 H, ArCH2), 7.34-7.46 (m, 5H, ArH), 7.64 (b s, 2H, NH2, exchange with D2O); MS (EI) calcd. m/z for C12H12N4O3 260.0908, found 260.0913; Anal.(C12H12N4O3) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[F:12][S:8]([F:13])([F:9])([F:10])([F:11])[C:6]1[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[CH:3]=[C:2]([O:1][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:7]=1
Reactant: CC(=O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(OCCOC2CCCCO2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
1-[3-Hydroxy-5-(pentafluorosulfanyl)phenyl]ethanone (O3.050; 700 mg) and 2-(2-bromo-ethoxy)tetrahydropyran (670 mg) were dissolved in DMF (15 ml), and sodium hydride (77 mg) was added. After stirring at RT for 2 h, the mixture was heated to 50° C. for 4 h and left to stand over the weekend. Then the DMF was drawn off and the residue was taken up in EA. The EA phase was washed with water, dried, filtered and concentrated. The crude product was purified using silica gel (100 g, n-heptane/EA 4:1). 813 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:74][CH2:75][CH2:76][CH2:77][N:78]1[CH:82]=[CH:81][N:80]=[CH:79]1>CN(C=O)C>[N:78]1([CH2:77][CH2:76][CH2:75][NH:74][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:17][CH2:18][CH2:19][CH2:20]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:30])[CH:82]=[CH:81][N:80]=[CH:79]1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Reactant: NCCCn1ccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)NCCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 1-(3-aminopropyl)imidazole (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with toluene/methanol (8:2), which after evaporation of the solvents under vacuum gave N-{4′-[(3-imidazol-1-ylpropylamino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (12 mg, 24%). NMR; δH [2H6]-DMSO 10.31,(1H, s), 8.60,(1H, t), 8.19,(1H, d), 7.93,(2H, d), 7.71,(1H, dd), 7.67,(2H, m), 7.45,(2H, d), 7.30,(1H, d), 7.22,(1H, s), 1.93,(6H, m). LCMS: retention time 2.24 min, MH+509.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([O:15]C)=O>CO>[OH:3][NH:2][C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)=[O:15]
Reactant: NO
Reactant: COC(=O)c1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(NO)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 25.4 g. (365 mmole) of hydroxylamine hydrochloride in one liter of methyl alcohol were added 39.4 g. (730 mmole) of sodium methylate. A slight exotherm occurred and sodium chloride precipitated. The solution was allowed to cool to room temperature, 50 ml. (365 mmole) of methyl 2-pyridinecarboxylate were added, and the reaction mixture was stirred overnight. The mixture was filtered to remove the salt precipitate and the filtrate was evaporated to dryness. The residue was dissolved in 100 ml. of water, pH 10.1, the solution acidified to pH 5.0 with concentrated hydrochloric acid. The solution was diluted with 500 ml. of isopropyl alcohol added dropwise and the additional sodium chloride precipitate was filtered. The filtrate was concentrated to about 100 ml. and the insoluble product was filtered. There were obtained 37.1 g. of the product which melted at about 58° C. to about 68° C. On chilling the filtrate an additional 12.5 g. of the product were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](N)[C:5](=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=O)[C:6]([OH:8])=[O:7].C(Br)C1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]=C(S(C)=O)C=1Cl)C(O)=O.C1(CBr)CC1>>[CH:26]1([CH2:25][NH:24][C:3]2[CH:4]=[C:5]([CH:9]=[C:10]([S:11]([CH3:14])=[O:13])[C:2]=2[Cl:1])[C:6]([OH:8])=[O:7])[CH2:27][CH2:31]1
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl
Reactant: CS(=O)c1cc(C(=O)O)cc(N)c1Cl
Agent: BrCC1CC1
Agent: BrCc1ccccc1
Product: CS(=O)c1cc(C(=O)O)cc(NCC2CC2)c1Cl

Procedure:
This product is prepared by replacing the 4-chloro-5-methylsulfonylanthranilic acid and the benzyl bromide employed in Example 4 by equivalent quantities of 3-amino-4-chloro-5-methylsulfinylbenzoic acid and cyclopropylmethyl bromide, respectively and following substantially the same procedure described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH:19]4[CH2:20][CH2:21][C:16]5([CH2:17][CH2:18]4)[C:11]3([CH2:12][CH2:13][N:14]([CH3:23])[C:15]5=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.B.CSC.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH:10]3[CH:19]4[CH2:20][CH2:21][C:16]5([CH2:17][CH2:18]4)[C:11]3([CH2:12][CH2:13][N:14]([CH3:23])[CH2:15]5)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC1C3CCC4(CC3)C(=O)N(C)CCC214
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cccc2c1OC1C3CCC4(CC3)CN(C)CCC214

Procedure:
The 9-methoxy-3-methyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one (V; R1 =Me, R2 =OMe, R3 =H) so obtained was heated under reflux with 0.7 mL of borane-methyl sulfide in tetrahydrofuran overnight. Conc. hydrochloric acid was added, the tetrahydrofuran was removed, and the residue was heated under reflux with 7 mL of acetic acid and 3 mL of conc. hydrochloric acid for two hours. The solvents were removed, water and toluene were added, and the aqueous layer was made basic and extracted with methylene chloride. Removal of the solvent and short-path distillation of the residue [150° bath, 0.5 μm (0.07 Pa)] gave 0.52 g of 9-methoxy-3-methyl-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethanobenzofuro[3,2-e]isoquinoline as a viscous oil that slowly solidified. NMR spectrum (220 MHz in CDCl3): τ3.1 (d/d, J=6.5/2.5 Hz, 1); 3.5 (m, 2); 5.7 (narrow m, 1); 6.2 (s, 3); 8.0 (s, 3); and 7.5-9.3 (m, 15).
Reaction SMILES: [CH3:1][CH:2]([C:4](=O)[C:5](=O)[CH:6]([CH3:8])[CH3:7])[CH3:3].[CH:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[NH2:17].O>C(O)(=O)C>[CH:2]([C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[N:18][C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:17]=1)([CH3:3])[CH3:1]
Reactant: NC1CCCCC1N
Reactant: CC(C)C(=O)C(=O)C(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1nc2c(nc1C(C)C)CCCC2

Procedure:
8.7 g of 2,5-dimethyl-3,4-hexanedione and 11.2 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 30 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 6.8 g of the title compound as a colorless oil.
Reaction SMILES: [I:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.O.[OH-].[Li+]>O1CCCC1.O>[I:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2ccc(OC)c(I)c2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1I)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To the solution of 0.4 g (0.93 mmol) of ethyl 8-iodo-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 8 mL of tetrahydrofuran was added a solution of 155 mg (3.7 mmol) of lithium hydroxide hydrate (LiOH—H2O) in 15 mL of water. The resulting solution was heated to reflux for one h. After cooling to room temperature, the volatiles were removed, the residue was acidified at 0° C. to pH=1.5 with dilute hydrochloric acid. The product was extracted with ethyl ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concd in vacuo to afford 0.30 g (81%) of a light yellow solid: 1H NMR (CDCl3/400 MHz) 7.67(s, 1H), 7.18(d, J=8.4 Hz, 1H), 6.51(d, J=8.4 Hz, 1H), 5.78(q, J=6.8 Hz, 1H), 3.92(s, 3H). MS (ESI+) 400.9 (M+1, 100). MS(ES−) 398.9(M−H, 100). HRMS (ES−) m/z calcd for (M−H; C12H7F3O4): 398.9336, found 398.9368.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 95%).
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH:10]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:15]=3[CH:16]=2)[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>N1C=CC=CC=1>[C:26]([O:11][CH:10]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:15]=2[CH:16]=1)[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:25][CH:24]=1)(=[O:28])[CH3:27]
Reactant: CC(C)c1ccc2oc(C(O)COc3ccc(C(=O)O)cc3)cc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(COc1ccc(C(=O)O)cc1)c1cc2cc(C(C)C)ccc2o1
Temperature: 0 °C

Procedure:
2-[1-Hydroxy-2-(4-hydroxymethylphenoxy)ethyl]-5-isopropylbenzofuran (10 g) obtained in Example 6 was dissolved in 100 ml of pyridine, the mixture was stirred at room temperature for 24 hours with 10 ml of acetic anhydride, poured into ice water, the mixture was acidified with concentrated hydrochloric acid and the crystals separated out therefrom were filtered, dried and recrystallized from ethyl acetate/n-hexane to give 8.2 g of crystals. M.p. 135°-137° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:3]1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C1CCN2C(=NCCC2)CC1>CCO>[C:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:3][C:2]1=[O:1])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)C1(CCC(=O)OC(C)(C)C)SC(Nc2ccccc2C(F)(F)F)=NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compounds were prepared according to the procedure reported in the literature: see S. Muthusamy Synth. Commun. 2002, 32, 3247. To a stirred solution of ethyl 4-oxo-2-(2-(trifluoromethyl)phenylamino)-4,5-dihydrothiazole-5-carboxylate (1.1 g, 3.3 mol), tert-butyl acrylate (Aldrich, 2.5 mL, 16.5 mmol) in EtOH (10 mL) was added DBU (Aldrich, 0.25 mL, 1.6 mmol). The mixture was stirred at r.t. overnight and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 461 (M+1).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:19](Cl)(Cl)=[S:20]>ClCCl>[C:1]1([N:11]=[C:19]=[S:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: S=C=Nc1cccc2ccccc12
Temperature: 25 °C

Procedure:
To the mixture of 1-naphthylamine (21.48 g), triethylamine (33.39 g), and dichloromethane (250 mL) was added a dicholomethane (50 mL) solution of thiophosgen (18.97 g) at bleow 20° C. over 30 minutes, and the mixture was stirred at room temperature. The reaction mixture was added into ice-water (1000 mL), extracted with diethyl ether (1000 mL). The extract was washed two times with brine (1000 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to obtain crude (1-naphthyl)isothiocyanate.
Reaction SMILES: C(OCC)(=[O:3])C.[CH2:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=2[CH:20]=1)[CH3:8].C1(CCCC2C=C[N+]([O-])=CC=2)C=CC=CC=1.Cl[O-].[Na+]>>[O:3]1[C@H:14]2[C@@H:15]1[C:16]([CH3:19])([CH3:18])[O:17][C:12]1[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:20][C:13]=12
Reactant: CCc1ccc2c(c1)C=CC(C)(C)O2
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [O-]Cl
Agent: [O-][n+]1ccc(CCCc2ccccc2)cc1
Product: CCc1ccc2c(c1)[C@H]1O[C@H]1C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution (2 mL) of ethyl acetate containing 100 mg (0.53 mmol) of 6-ethyl-2,2-dimethyl-2H-1-benzopyran (synthesized according to the method described in Jananese Patent Application Laid-open No. Sho 62-273972), salen manganese complex (17 mg, 0.016 mmol), 4-(3-phenylpropyl)-pyridineoxide) (12 mg, 0.053 mmol) and aqueous sodium hypochlorite solution (0.96 g, 1.14 Kg/mol, 1.1 mmol) were added at room temperature, and stirred for two hours at room temperature. After Celite filtration upon addition of water, organic phase was separated, washed with aqueous saturated sodium chloride solution, and dried over anhydride sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (chloroform) to obtain 75 mg of the intended compound in brown oily substance (Yield 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=2[N:26]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1>>[NH:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:21])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4[nH]3)cc2)cc1)C(=O)O
Yield: 46.9 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (64 mg, 0.21 mmol) and 2-chloro-1H-benzimidazole (37.6 mg, 0.25 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 40.7 mg (48%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 11.05 (br s, 1H), 8.05 (d, 2H), 7.85 (m, 4H), 7.65 (d, 2H), 7.40 (m, 2H), 7.10 (m, 2H), 3.35 (s, 2H), 1.25 (s, 6H). LC-MS m/z 414.3 (MH+), ret. time 2.27 min.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH2:25])[C:22]([Cl:26])=[CH:21][C:17]=1[C:18]([OH:20])=O.[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[CH:27]1([CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[C:23]([NH2:25])=[CH:24][C:16]=3[O:15][CH3:14])[CH2:36][CH2:35]2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: NC1CCN(CC2CCCCC2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Triethylamine (5.6 ml; 0.04 moles) and ethyl chloroformate (3.84 ml; 0.04 moles) were added successively to a stirred suspension of 2-methoxy-4-amino-5-chlorobenzoic acid (8 g; 0.04 moles) in anhydrous tetrahydrofuran (300 ml) whilst maintaining the temperature beween -5° and -10° C. After stirring at this temperature for 0.5 hours, a solution of 1-cyclohexylmethyl-4-aminopiperidine (7.85 g; 0.04 moles) in anhydrous tetrahydrofuran (50 ml) was added, the temperature was maintained at -5° to -10° C. for 1 hour and then allowed overnight to reach room temperature. The solvent of the mixture was removed in vacuo, the residue poured into water, extracted with chloroform and the organic layer washed with water. The chloroformic solution was dried (Na2SO4) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N-(1-Cyclohexylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (8 g) was thus obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]([F:32])([F:31])[C:13]1[CH:14]=[C:15]([C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26]/[C:27](=[N:28]\[C:29]#[N:30])/[C:21]=3[CH:20]=2)[CH:16]=[CH:17][CH:18]=1>CO>[CH3:2][N:3]1[C:29]([NH2:30])=[N:28][C:27]2([C:21]3[CH:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:31])[F:32])[CH:14]=4)[S:23][C:22]=3[CH2:24][CH2:25][CH2:26]2)[O:4]1
Reactant: CNO
Reactant: N#C/N=C1\CCCc2sc(-c3cccc(C(F)(F)F)c3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1OC2(CCCc3sc(-c4cccc(C(F)(F)F)c4)cc32)N=C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of methylhydroxylamine hydrochloride (23 mg, 0.28 mmol) in methanol (2 mL) was added potassium carbonate (44 mg, 0.32 mmol) followed by (E)-N-(2-(3-(trifluoromethyl)phenyl)-6,7-dihydrobenzo[b]thiophen-4(5H)-ylidene)cyanamide (50 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo and the crude residue partitioned between dichloromethane and water. The product was extracted into dichloromethane (×3). The organic extracts were combined, dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified using preparative HPLC to give the title compound as yellow solid (34.2 mg, 58%). (regioisomeric mix with 2′-methyl-2-(3-(trifluoromethyl)phenyl)-6,7-dihydro-2′H, 5H-spiro[benzo[b]thiophene-4,3′-[1,2,4]oxadiazol]-5′-amine). 1H NMR δ (ppm)(DMSO-d6): 7.87-7.80 (2H, m), 7.64-7.58 (2H, m), 7.34 (1H, s), 6.12 (2H, s), 2.94 (3H, s), 2.80-2.60 (2H, m), 1.93-1.80 (3H, m), 1.80-1.69 (1H, m). HPLC (Method a) Rt 8.05 (min) m/z 368 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[NH2:20])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(O[C:24]([CH2:26][C:27]1[N:31]([CH3:32])[C:30]2[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:29]=2[N:28]=1)=O)C>>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][C:4]1[CH:17]=[CH:18][C:19]2[NH:20][C:24]([CH2:26][C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][C:35]([C:37]([OH:39])=[O:38])=[CH:36][C:29]=4[N:28]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: CCOC(=O)Cc1nc2cc(C(=O)O)ccc2n1C
Reactant: Nc1ccc(CN2C(=O)c3ccccc3C2=O)cc1N
Product: Cn1c(Cc2nc3cc(CN4C(=O)c5ccccc5C4=O)ccc3[nH]2)nc2cc(C(=O)O)ccc21
Yield: 48 %

Procedure:
2-(3,4-Diaminobenzyl)isoindole-1,3-dione, prepared as in Example 2(d), was reacted with 2-ethoxycarbonylmethyl-1-methyl-1H-benzoimidazole-5-carboxylic acid under conditions similar to that set forth in Example 2(e) to provide 2-[5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylmethyl]-1-methyl-1H-benzoimidazole-5-carboxylic acid (48% yield); 1H-NMR (300 Mhz, DMSO-d6): 8.10 (s, 1H), 7.80-7.84 (m, 5H), 7.57 (d, 1H, J=10.0 Hz), 7.40 (br s, 2H), 7.10 (br s, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 3.79 (s, 3H).