Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(O)(=O)C>[OH:15][C:10]1[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNc1ccc(I)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Temperature: 125 °C
Yield: 8.3 %

Procedure:
4-Iodo phenyl hydrazine (8.97 g, 36.4 mmol) was added in one portion to a stirred mixture of phthalic anhydride (5.0 g, 33 mmol) in acetic acid (40 ml) at room temperature. The reaction mixture was heated to 125° C. for 2 hours, and then allowed to cool to room temperature. The suspension was poured into H2O (100 ml) and the resulting solid was removed by filtration. The mother liquor was acidified with conc. HCl. The resulting solid was collected by filtration and dried in vacuum to give the title compound (1.0 g, 8% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.91 (1H, br. s), 8.30 (1H, d), 7.91–8.03 (3H, m), 7.83 (2H, d), 7.51 (2H, d); MS (ESI+)=365.0 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17].Cl>CO.CC(O)=O>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]1[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][C:16]2=1
Reactant: O=C1CCCCC1=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
4-Bromophenyl hydrazine hydrochloride (0.3 g, 1.3 mmol) in MeOH (3 mL) was heated to 60° C. and 1,2-cyclohexanedione (0.16 g, 1.4 mmol), dissolved in AcOH (4 mL) and conc. HCl (1.5 mL) were added while maintaining the temperature at 60° C. After the addition was completed, the reaction mixture was cooled to room temperature and stirred for 12 h during time a solid precipitated out. The mixture was basified with aq NaHCO3 and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography to give the title compound as a pale yellow solid (0.080 g, 22%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.8 (bs, 1H), 7.8 (s, 1H), 7.43 (dd, J=10.0, 2.0 Hz, 1H), 7.24 (d, J=9.5 Hz, 1H), 2.98 (t, J=8.0 Hz, 2H), 2.63 (t, 8.0 Hz, 2H), 2.24 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1>CN(C=O)C>[Br:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([OH:11])=[C:6]([C:7]([N:36]2[CH2:37][C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35]2)=[O:9])[CH:10]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)cc1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 42.1 %

Procedure:
A solution of 5-bromo-2,4-dihydroxy-benzoic acid (520 mg, 2.33 mmol) in DMF (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (471 mg, 2.45 mmol) then HOBt (362 mg, 2.68 mmol). After 25 min. 2,3-dihydro-1H-isoindole (0.5 mL, 2.63 mmol) was added then the mixture was stirred at r.t. for 18 h. The solvent was removed in vacuo then the residue was taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and brine then dried (MgSO4) and concentrated. The residue was triturated with methanol to afford the title compound as a grey solid (328 mg, 44%). 1H NMR (DMSO-d6) 10.45 (1H, s), 10.32 (1H, s), 7.36 (1H, br.s), 7.35 (1H, s), 7.28 (3H, br.s), 6.59 (1H, s), 4.77 (2H, br.s), 4.71 (2H, br.s). MS: [M+H]+ 332/334.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].O[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([CH:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=2)=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)C(=O)Nc1ccc(CCO)cc1
Reactant: CCOC(=O)C(C#N)Cc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C#N)Cc1ccc(OCCc2ccc(NC(=O)C(C)C)cc2)cc1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
Ethyl 2-cyano-3-(4-hydroxyphenyl)propanoate (1 g, 4.56 mmol) and N-[4-(2-hydroxyethyl)phenyl]-2-methylpropanamide (1.42 g, 6.85 mmol) were mixed in dichloromethane (40 ml). 1,1′-(Azodicarbonyl)dipiperidine (2.3 g, 9.12 mmol) and triphenylphosphine (2.4 g, 9.15 mmol) were then added respectively. The mixture was stirred overnight and filtered. The filtrate was evaporated to dry in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane as eluant gave 0.5 g desired product, yield 27%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[O:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH2:23]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:23][C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:14]2[O:13][CH:17]=[CH:16][N:15]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccsc1-c1ncco1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2ncco2)cc1

Procedure:
2-(4-methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid 64 mg, 0.385 mmol) and 2-(oxazol-2-yl)thiophen-3-amine (64 mg, 0.385 mmol) according to protocol A. Retention time (min)=6.845, method [7], MS (ESI) 315.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.59 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.28-7.37 (m, 3H), 6.94-6.99 (m, 3H), 3.85 (s, 3H), 3.66 (s, 2H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([NH:11][NH2:12])[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].F[C:14]1[CH:21]=[C:20](SCCC)[CH:19]=[C:18]([O:26][CH3:27])[C:15]=1[CH:16]=O.CS(C)=O>O>[CH3:27][O:26][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]2[C:15]=1[CH:16]=[N:12][N:11]2[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1
Reactant: CCCSc1cc(F)c(C=O)c(OC)c1
Reactant: CCCSc1nccc(NN)n1
Solvent: O
Solvent: CS(C)=O
Product: CCCSc1nccc(-n2ncc3c(OC)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Propylsulfanyl-pyrimidin-4-yl)-hydrazine (7.036 g), 2-fluoro-6-methoxy-4-propylsulfanyl-benzaldehyde 5.524 g) and DB 16.373 g) were added to DMSO (70 mL) and the mixture was stirred at room temperature for one hour, then stirred at 80° C. for one hour. The mixture was cooled, diluted with water, and filtered. The collected solid was washed with water, and dried under reduced pressure to give 4-methoxy-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[C:21]([F:27])[C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:26][C:22]1[C:21]([F:27])=[C:20]2[NH:19][C:18](=[O:28])[C:10]3([CH:9]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1c2ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (0.91 g, 1.7 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (0.95 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][N:12]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][NH:14][C:13]2=[O:25])=[CH:5][CH:4]=1.[N:26]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[NH2:26][N:14]1[CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:12]([CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]1=[O:25]
Reactant: COc1ccc(CCCN2C(=O)NCC2c2ccc(OC)cc2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCCN2C(=O)N(N)CC2c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 109.3 %

Procedure:
To a solution of 1-[3-(4-methoxyphenyl)propyl]-5-[(4-methoxy)-phenyl]-2-imidazolidinone (0.6 g, 1.75 mmol) in acetic acid (15 mL) is added dropwise a solution of NaNO2 (0.12 g, 1.8 mmol) in water (1 mL). The mixture is cooled in an ice bath to 5° C. and zinc dust (0.6 g, 9 mmol) is added in portions (starting with 0.5 g addition) over 50 minutes at less than 12° C. The reaction is stirred for 5 minutes and the ice bath is removed. The reaction temperature rises quickly to about 20° C. and the reaction is maintained below about 32° C. with an ice bath. The reaction is stirred for 70 minutes at 20° C. to 27° C. and any unreacted zinc is removed by filtration. The volume of the filtrate is reduced in vacuo then diluted with dichloromethane (15 mL). To the stirred mixture is added concentrated ammonium hydroxide (2 mL), keeping the temperature below about 32° C. with an ice bath. The organic phase is separated, washed with brine, dried (Na2SO4), and concentrated to afford 0.68 g (quantitative yield) of the desired compound as a colorless oil which is used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N+:23]([O-:26])=[C:22]([NH:27][C:28](=O)C)[CH:21]=3)[C:12]2=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].C(Cl)(Cl)=[S:38]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:28](=[S:38])[N:27]=[C:22]4[CH:21]=3)[C:12]2=[O:31])=[CH:9][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)cc[n+]1[O-]
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
To a solution of 240 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}-1-oxidopyridin-2-yl)acetamide obtained in stage a) below in 6 mL of ethanol are added 109 mg of sodium hydrogen carbonate and 75 mg of thiocarbonyl dichloride. After stirring for 2 hours 30 minutes, the solid in suspension is filtered off, washed with ethanol and dried. 220 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazol-idine-2,4-dione are obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NC1CC(F)(F)CC1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 120 mg, 0.349 mmol) in dry DMSO (1.2 ml) was added 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 70 mg, 0.38 mmol) and DIPEA (183 μl, 1.05 mmol). The reaction mixture was heated in a sealed vial at 140° C. for 17 hours then partitioned between ethyl acetate and water. The organics were washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate in petrol) and then was chirally separated using SFC (Waters prep30/MS system using 10% Ethanol, Daicel AD 10 mm id×250 mm long columns at 30 ml/min, 40° C. and 100 bar) to afford the title compound as a single enantiomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:10])=[CH:6][CH:7]=1
Reactant: CNC1CCCCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C1CCCCC1
Temperature: 80 °C
Yield: 95.2 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (500 mg, 3.08 mmole) in 8 mL of dry acetonitrile is 384 mg (3.39 mmol) of N-methylcyclohexylamine followed by 468 mg (3.39 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 700 mg (95% yield) of (6-Chloro-pyridin-3-ylmethyl)-cyclohexyl-methyl-amine. C13 NMR 26.1, 26.6, 28.9, 37.7, 54.5, 62.8, 124.1, 135.1, 139.5, 149.9; MS 239.3 (M+H).
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[CH2:5][CH2:6][CH2:7][C:8]([OH:17])([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:9]\1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]2[N:44]=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)([OH:17])[C:9]=3[N:43]=2)[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)/C=C1\CCCC(O)(c2cccnc2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(O)(c2cccnc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 6-[1-dimethylamino-meth-(E)-ylidene]-2-hydroxy-2-pyridin-3-yl-cyclohexanone (59 mg, 0.24 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (74 mg, 0.20 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (54 mg, 63%). MS ISP (m/e): 429.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.63 (s, 1H), 8.51 (s, 1H), 8.42 (m, 2H), 7.72 (s, 1H), 7.68 (d, 1H), 7.62 (s, 1H), 7.33 (dd, 1H), 7.04 (s, 2H), 6.97 (s, 1H), 5.95 (s, 1H), 5.76 (s, 1H), 3.39 (s, 3H), 2.75 (m, 3H), 2.12 (s, 3H), 2.02 (m, 3H), 1.75 (m, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS([O-])=O.[Na+].[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:25]#[N:26].C(O)C>O>[O:1]([C:8]1[CH:15]=[CH:14][C:11]([C:12]2[NH:30][C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[N:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2[nH]c(-c3ccc(Oc4ccccc4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
To 4-phenoxybenzaldehyde (4.0 g, 0.020 mol) was added 20 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzonitrile (3.36 g, 0.0252 mol) and ethanol (50 mL) were added. The mixture was refluxed for 4 h. The reaction was then poured into water. The precipitate was filtered and recrystallized from ethyl acetate to afford 3.6 g (57%) of 2-(4-phenoxyphenyl)-1H-benzimidazole-5-nitrile.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C1(C)C=CC=CC=1.[F-].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 96.8 %

Procedure:
To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) and 4-fluorophenylboronic acid (4.6 g, 32 mmol) in 4:1 toluene:water (100 mL) were added potassium fluoride (3.8 g, 66 mmol) and Pd(PPh3)4 (2.5 g, 2.2 mmol). The resulting mixture was stirred at reflux for 12 h. The mixture was cooled to room temperature and extracted with ethyl acetate (30 mL*3). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the crude residue by silica gel chromatography gave 4′-fluorobiphenyl-4-carbonitrile (4.2 g) as a colorless solid. 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 4H), 7.63-7.60 (m, 2H), 7.15-7.10 (m, 2H).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:26]([CH2:28]O)[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:15]=2[N:30]=1>C(Cl)Cl.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:27][CH:26]([CH2:28][F:7])[N:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([F:25])[C:23]=4[CH:24]=[C:16]3[C:15]=2[N:30]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Solvent: O
Solvent: ClCCl
Product: FCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
DAST (64 mg, 0.29 mmol) was added to a solution of (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methanol (60 mg, 0.2 mmol) in CH2Cl2 (0.5 mL) at −78° C. under N2. The mixture was stirred at −78° C. for 1 hour. The mixture was then heated to reflux and stirred for another 3 hours. The mixture was then diluted with water (30 mL) and extracted with CH2Cl2 (15 mL*3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=4:1) to provide 2-chloro-11-fluoro-6-(fluoromethyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (30 mg, yield: 50.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.29˜7.33 (m, 2H), 7.13˜7.20 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.78˜6.83 (m, 1H), 6.46˜6.51 (m, 1H), 4.35˜4.63 (m, 2H). MS (M+H)+: 307/309.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: O=C1OC(c2ccccc2)(c2ccc(-c3ccccc3)cc2)C(O)=C1OCc1ccccc1
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: O=C1OC(c2ccccc2)(c2ccc(-c3ccccc3)cc2)C(O)=C1O
Yield: 37.9 %

Procedure:
Hydrogenolysis of 500 mg of 5-[(1,1'-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-phenyl-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 150 mg (38% yield) of 5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-phenyl-2(5H)-furanone as colorless needles: mp 188-191° C. dec.(CHCl3 /hexanes). 1H NMR (acetone-d6) δ 7.75-7.36 (m, 14H). 13C NMR (acetone-d6) δ 168.34, 154.84, 141.50, 140.66, 140.30, 139.42, 129.18, 128.74, 128.59, 127.92, 127.40, 127.25, 127.07, 119.45, 84.59. Anal Calcd for C22H16O4 : C, 76.73; H, 4.68. Found: C, 76.44; H, 4.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:14])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: Nc1ccc2c(c1)OCCO2
Product: O=C(Nc1ccc2c(c1)OCCO2)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 10(c). 6-Bromo-naphthalene-2-carboxylic acid (0.5 g, 2 mmol, Lancaster) reacted with 1,4-benzodioxan-6-amine (0.332 g, 2.2 mmol, Aldrich) to give the title compound as a light-yellow solid. Mp 222.7° C. MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (8.00 g) in anhydrous DMF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g) in anhydrous DMF (200 ml), and the resulting mixture was stirred at room temperature for 80 minutes. To the reaction solution, 2-iodopropane (4.03 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. Sodium hydride (1.08 g) was added to the reaction solution and thereafter 2-iodopropane (4.03 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 6 hours. Water was added to the reaction solution and the resulting mixture was extracted twice with ethyl acetate. Organic layers were washed 4 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:cyclohexane, cyclohexane/ethyl acetate=50/1). The obtained solid was recrystallized from hexane to obtain N-(4-iodophenyl)-N-isopropylpyrimidin-2-amine (7.06 g). NMR (H1, CDCl3): δ 1.14 (3H, s), 1.16 (3H, s), 5.12-5.19 (1H, m), 6.52 (1H, t, J=4.6 Hz), 6.88-6.92 (2H, m), 7.74-7.77 (2H, m), 8.29 (2H, d, J=4.6 Hz)