Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH:3]=1.[I:12]N1C(=O)CCC1=O.CCCC[N+](CCCC)(CCCC)CCCC.[FH:37].F.[F-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH:10]([F:37])[CH2:11][I:12])[CH:3]=1
Reactant: C=CCCc1cccc(Br)c1
Reactant: O=C1CCC(=O)N1I
Reactant: F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: FC(CI)CCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of 0.245 gm (1.16 mmol) of 1-bromo-3-but-3-enylbenzene in CH2Cl2 at 0° C. was treated with 0.39 gm (1.74 mmol) of N-iodosuccinimide and 1.05 gm (1.74 mmol) of 50% wt/wt tetrabutylammoniumdihydrogen trifluoride in CH2Cl2, stirred at 0° C. for 2 h, warmed to room temperature over a 1 h period and poured into CH2Cl2. The resultant organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure. Chromatography of the concentrate on silica gel with a gradient of hexanes to 7.0% EtOAc-hexanes afforded 1-bromo-3-(3-fluoro-4-iodo-butyl)-benzene as an oil, 0.40 gm (50% yield); 1H NMR (400 MHz, CDCl3) δ: 2.03 (m, 2H), 2.74 (m, 2H), 3.29 (dd, 2H, J=5.4, 19.1 Hz), 4.47 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[C:13]([NH2:16])(=[S:15])[CH3:14].C(=O)(O)[O-].[Na+]>C(O)C.CCOCC.CCCCCC>[CH3:14][C:13]1[S:15][CH:8]=[C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:16]=1
Reactant: CC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCO
Product: Cc1nc(-c2ccc(C#N)cc2)cs1
Yield: 92.9 %

Procedure:
Suspend 4-cyanophenacyl bromide (515 mg, 2.23 mmol) in ethanol (15 mL). Add thioacetamide (171 mg, 2.23 mmol) and sodium bicarbonate (187 mg, 2.23 mmol) and heat the mixture under reflux for 2 h. Concentrate in vacuo and dissolve the residue in DCM. Wash the organic fraction with water, dry over Na2SO4, filter and concentrate to give a solid. Suspend the solid in ether/hexane and filter under vacuum washing with hexane to obtain the desired intermediate as a white solid (415 mg, 93%). GC-MS m/z: 200 (M+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][S:13](=S)(OC)=O>O.C(O)C.CCOCC>[CH3:12][S:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COS(C)(=O)=S
Reactant: O=C(O)Cc1ccccc1S
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CSSc1ccccc1CC(=O)O
Reaction time: 20 h
Yield: 100.7 %

Procedure:
To a solution of (2-mercaptophenyl)acetic acid (449 mg) in H2O (15 mL) and ethanol (7 mL) was added methyl methanethiosulfonate (372 mg, 2.93 mmol). After stirring for 20 hours, the reaction mixture was diluted with ether and washed with 1 N KOH twice. The water layers were combined and acidified to pH 2 with 5 N hydrochloric acid. This solution was extracted with CH2Cl2 three times. The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford 576 mg (100% yield) of the (2-methyl disulfanylphenyl)acetic acid product in the form of a yellow oil: 1H NMR (400 MHz, CDCl3) δ (ppm): 2.42 (s, 3H), 3.92 (s, 2H), 7.10-7.40 (m, 3H), 7.80 (d, J=7.6 Hz, 1H), 10.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 22.7, 38.9, 127.8, 128.1, 128.3, 128.8, 130.4, 130.8, 130.9, 177.1. HRMS (EI): m/e calcd. for C9H10O2S2: 214.012223, Found: 214.012637 (Δ=−1.9 ppm).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH:25]1[O:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[O:27]1[CH2:26][CH:25]1[CH2:24][O:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2cc(Nc3ccc(O)cc3)ncn2)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[4'-hydroxyanilino]6-(3'-methylanilino)pyrimidine (1.14 g), 1-bromo-2,3-epoxypropane-(0.5 ml) and potassium carbonate (1.24 g) in DMSO (12 ml) was stirred at ambient temperature for 16 hours to give 4-[4'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine (0.70 g);
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C.O>ClCCl>[Cl:19][CH2:20][C:21]([N:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][C:2]=1[Cl:1])[CH3:5])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(OCOCC[Si](C)(C)C)cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CCl)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-N-methyl-4-{[2-(trimethylsilyl)ethoxy]methoxy}aniline (1.00 g) in dichloromethane (20.0 mL) were added chloroacetyl chloride (0.415 mL) and triethylamine (0.872 mL) under ice-cooling, followed by stirring for 1 hour under ice-cooling. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-N-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methylacetamide (1.08 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O=S(Cl)Cl.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: OCc1ccccc1
Reactant: O=C(O)C1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of tetrahydropyran-4-yl-carboxylic acid (910 mg, 6.99 mmol) and SOCl2 (5.0 mL) was stirred for 1 h at 60° C. and concentrated in vacuo. To the residue were added benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 mL) at ambient temperature. The resulting mixture was stirred for 13 h at ambient temperature and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluting with hexane/ethyl acetate (2:1)) to give 1.08 g (70%) of the title compound as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)=[O:26]>>[OH:21][CH2:22][CH2:23][NH:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)=[CH:4][CH:3]=1)[CH:31]=[CH:30]2)=[O:26]
Reactant: O=C(NCCO)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)C1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(C(=O)NCCO)ccc43)nc2)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using tert-butyl 3-((6-chloropyridin-3-yl)oxy)pyrrolidine-1-carboxylate and N-(2-hydroxyethyl)-1H-indole-5-carboxamide; MS: 466.5 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(S)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Oc1ccc(SC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 276.2 %

Procedure:
To a solution of 4-hydroxythiophenol (10 g, 79 mmol) and p-toluenesulphonic acid (100 mg) in dichloromethane (100 ml) was added dihydropyran (16.7 g, 19.8 mmol) and the mixture stirred at room temperature for 18 hours. The mixture was concentrated in vacuo and the residue dissolved in THF (100 ml) and 0.5 M sulphuric acid (20 ml). The mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (200 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo. Purification by flash column chromatography on silica eluting with 25% diethyl ether in hexane afforded the title compound as a white solid (11.5 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Cl.[NH2:28][C@H:29]([C:35]([OH:37])=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34]>O>[NH2:28][C@H:29]([C:35]([OH:37])=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: NCCCC[C@H](N)C(=O)O
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 139.8 %

Procedure:
Sodium 7-[2-(2-aminothiazol-4-yl)-2- methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.21 g.) was added to a solution of lysine hydrochloride (0.55 g.) in water (12 ml.). The solution was lyophilized to give a lysine salt of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.6 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34].[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([N:36]([CH3:37])[CH3:35])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:34]
Reactant: CNC
Reactant: CN(C)CCNc1nc(-c2cccc(C(=O)O)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNc1nc(-c2cccc(C(=O)N(C)C)c2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 40.4 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)benzoic acid (23 mg, 0.05 mmol) in CH2Cl2 (3 mL) were added dimethylamine (2.0 M soln. in THF, 0.0275 mL, 0.055 mmol), HATU (20 mg, 0.052 mmol) and diisopropyl ethyl amine (0.05 mL, 0.3 mmol). The reaction mixture was stirred over night. The reaction mixture was diluted with CH2Cl2 (5 mL) and water (5 mL) and shaked. The layers were separated and the organic layer was washed with brine (8 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) then provided the title compound as a white solid (10 mg, 41%). LC-MS m/z 496 (M+H)+; 1H-NMR (MeOD) δ 2.15 (s, 6H), 2.36 (m, 2H), 3.15 (s, 3H), 3.06 (s, 3H), 3.23 (m, 2H), 4.46 (s, 2H), 7.14 (m, 2H), 7.12 (m, 1H), 7.56 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]([C:13]([Cl:16])([F:15])[F:14])=[CH:10][C:11]=1[OH:12])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH3:28]>CC(C)=O>[Cl:16][C:13]([F:14])([F:15])[C:9]1[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([O:12][CH2:27][CH3:28])[CH:10]=1
Reactant: CCI
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OCC)cc(C(F)(F)Cl)nc1C(F)(F)F
Yield: 82.2 %

Procedure:
This product was prepared as described in Example 4, 25.5 g (0.080 mol) of product of Example 3, 14.3 g (0.103 mol) of K2CO3, 37.5 ml (0.470 mol) of ethyl iodide in 100 ml of acetone were reacted affording 22.86 g of oil which was purified by HPLC using 3% ethyl acetate/cyclohexane as eluting solvent to give 14.73 g of solid. Crystallization in hot hexane gave 11.11 g (41.6%) of solid. A portion (0.98 g) of this solid was kugelrohr distilled at 29 Pa, pot temperature 70° C., to give 0.81 g of product as a white solid; mp 54.5°-56.5° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH:7]([CH:30]1[CH2:32][CH2:31]1)[CH2:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:16]=2)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:30]1([CH:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[C:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=3)=[O:11])[C:6]([OH:33])=[O:5])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C1CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC(C(=O)O)C1CC1)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
A mixture of 2-cyclopropyl-3-[(4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-propionic acid tert-butyl ester (52 mg) and TFA (2 mL) in DCM (2 mL) was stirred at rt for 3 h; then the mixture was concentrated and resulting residue was treated with water; the solids were collected via filtration and air dried to give desired product as white solids (37 mg). LC-MS ESI+: 393 (M+1)+.
Reaction SMILES: O.[CH3:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])=O.O.[NH2:14][CH2:15][C:16]([O-:18])=[O:17].NCC([O-])=O.[Zn+2:24]>C(O)C>[Zn:24].[OH:12][C:6]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=1[CH2:3][CH2:2][NH:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: [Zn+2]
Reactant: NCC(=O)[O-]
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: O
Solvent: CCO
Product: O=C(O)CNCCc1ccc(O)cc1O
Product: [Zn]

Procedure:
Ingredients. (1) Water 66.18 (2) Ethanol 30.0 (3) Resacetophenone 1.5 (4) Zinc Bis-glycinate Hydrate 2.32. Procedure. The mixture of all ingredients is heated at 80 to 85 C for 2 hours. It is then hydrogenated over Pt catalyst, and after filtration of catalyst N-[(2,4-dihydroxyphenyl)ethyl]glycine zinc complex is obtained.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)=[CH:14][N:13](CO)[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:23](=O)([O-:25])[O-:24].[K+].[K+]>C(#N)C>[CH:23]([OH:25])=[O:24].[N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:20]=[N:19][NH:18][CH:17]=4)=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: OCn1cc(-c2cn[nH]c2)c2c(N3CCOCC3)ncnc21
Agent: [K+]
Solvent: CC#N
Product: O=CO
Product: c1nc(N2CCOCC2)c2c(-c3cn[nH]c3)c[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [4-(morpholin-4-yl)-5-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methanol (C21) (from the previous step, 0.10 g, ≦0.32 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.34 g, 2.5 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the filter cake was washed with ethyl acetate (3×20 mL). The combined filtrates were concentrated in vacuo; purification via preparative HPLC (Column: DIKMA Diamonsil(2) C18, 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: acetonitrile; Gradient: 0% to 17% B) afforded the product as a pale solid. Yield: 36 mg, 0.11 mmol, 34% over 2 steps. LCMS m/z 271.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 10.72 (brs, 1H), 8.47 (s, 1H), 7.78 (s, 2H), 7.19 (s, 1H), 3.60-3.67 (m, 4H), 3.41-3.48 (m, 4H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].OO.C(OCC)C>O1CCCC1.O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:15]([OH:17])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C(CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Yield: 95 %

Procedure:
50.6 g of 3-(4-phenoxyphenyl)-5-phenylpentan-2-one was dissolved in 1280 ml of tetrahydrofuran, and 180 ml of a 1M tetrahydrofuran solution of tri-sec-butyllithium borohydride was added under cooling to -78° C. with stirring, followed by stirring at the same temperature for one hour. To the reaction solution, 224 ml of a 4N sodium hydroxide aqueous solution was added under cooling with ice with stirring, and then 118 ml of a 30% hydrogen peroxide aqueous solution was gradually dropwise added, followed by stirring at 0° C. for one hour. Ethyl ether and water were added to the reaction solution, followed by extraction. The organic layer was washed with a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 47.2 g (yield: 95%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [C:1]1([C:7]([O:9][C:10]2[CH:27]=[CH:26][C:25]3[C@@H:24]4[C@H:15]([C@H:16]5[C@@:20]([CH2:22][CH2:23]4)([CH3:21])[C@@H:19]([O:28][C:29]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[O:30])[CH2:18][CH2:17]5)[CH2:14][CH2:13][C:12]=3[CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][I:38]>CC(C)=O>[I-:38].[CH3:37][N+:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:29]([O:28][C@H:19]2[CH2:18][CH2:17][C@H:16]3[C@H:15]4[C@H:24]([CH2:23][CH2:22][C@:20]23[CH3:21])[C:25]2[CH:26]=[CH:27][C:10]([O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])=[CH:11][C:12]=2[CH2:13][CH2:14]4)=[O:30])[CH:32]=1
Reactant: CI
Reactant: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Solvent: CC(C)=O
Product: C[n+]1cccc(C(=O)O[C@H]2CC[C@H]3[C@@H]4CCc5cc(OC(=O)c6ccccc6)ccc5[C@H]4CC[C@]23C)c1
Product: [I-]

Procedure:
The product of Example 73 (1.5 9, 3.1 mmol) was suspended in 2.5 mL of acetone. Then, 2 mL of methyl iodide were added and the reaction mixture was refluxed overnight. The yellow solid (1.8 g, 93%) was collected by filtration and dried in vacuo. UV, NMR and elemental analyses confirmed that the product had the assigned structure: ##STR108##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Br:27])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][CH2:37][OH:38]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:35][CH2:36][CH2:37][OH:38])=[C:22]([Br:27])[CH:21]=1)[C:9]([NH2:18])=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(O)c(Br)c1)C(=O)OC(C)(C)C
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N=C(N)N(Cc1ccc(OCCCO)c(Br)c1)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 1,2-bis(tert-butoxycarbonyl)-1-[3-bromo-4-hydroxybenzyl]-guanidine (for synthesis, see, for example, Purohit et al., International PCT Patent Publication No. WO2008/083056, incorporated herein by reference) (2.0 g, 4.51 mmol) dissolved in anhydrous DMF (45 mL) was added K2CO3 (1.12 g, 8.13 mmol), and 3-bromopropanol (816 mg, 5.87 mmol) and the reaction mixture warmed to 50° C. using an oil bath. After 2 h, the reaction mixture was diluted with water (30 mL), and the aqueous layer separated then extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to a solid. The crude material was purified using silica gel chromatography (4:1 to 3:2 hexanes:EtOAc) to yield a white solid product (2.00 g, 88% yield). 1H NMR (CDCl3, 600 MHz): δ 9.42 (brs, 1H), 9.27 (brs, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.26 (m, 1H), 6.85 (d, J=2.4 Hz, 1H), 5.08 (brs, 2H), 4.19 (t, J=5.4 Hz, 2H), 3.92 (m, 2H), 2.16 (m, 1H), 2.18 (m, 2H), 1.51 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3, 150 MHz): δ 163.8, 160.8, 155.0, 154.3, 144.8, 133.1, 132.6, 127.9, 113.0, 111.7, 84.7, 79.2, 67.8, 60.6, 46.7, 31.9, 28.5, 28.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[Br:43][C:44]1[CH:45]=[C:46]([C@H:50]([NH:52][C:35]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[C:2]([Cl:1])[CH:3]=2)=[O:41])[CH3:51])[CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: C[C@@H](N)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4cccc(Br)c4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (78 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(3-bromophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (41 mg, yield 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12](O)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:20][CH3:21])=[CH:15][CH:14]=2)[CH:19]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Yield: 94.5 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 3.80 mmol) in POCl3 (5.31 ml, 57.0 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum to give 1-chloro-3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinoline (1.2 g, 95% yield). δ ppm 1H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (d, J=9.3 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 8.02 (dd, J=8.7, 2.4 Hz, 1H), 7.27-7.24 (m, 1H), 7.13 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 3.99 (s, 6H); MS: MS m/z 334.1 (M++1).