Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[C:18]([CH3:41])=[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=2)[C:20]([CH3:32])=[C:21]([Cl:31])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[Cl:31][C:21]1[C:20]([CH3:32])=[C:19]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:34]=2)[C:18]([CH3:41])=[C:17]([Cl:16])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Cc1c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(Cl)c(OCCCS(C)(=O)=O)c(Cl)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.237 g, 1.14 mmol), {3′,5′-dichloro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.475 g, 1.14 mmol) and tributylphosphine (0.453 mL, 1.82 mmol) in toluene (18 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.459 g, 1.82 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (9 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.622 g, yield 89%) as a yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CC(C)=O>[OH:18][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.8 %

Procedure:
To a solution of 8-(4-iodo-phenyl)-1,4 dioxa-spiro[4.5]decan-8-ol (2 g) in acetone (10 mL) was added 5% HCl (20 mL) and the mixture was stirred at rt for 14 hours. The mixture was neutralized with 1N NaOH to pH 7, concentrated on rotvap, and then extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo to provide 4-hydroxy-4-(4-iodophenyl)cyclohexanone (1.7 g, 98%). LCMS: 317.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@H:10]([CH3:13])[CH2:11]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1ccccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-2-{[(2S)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]([CH2:17]O)([CH2:15]O)[CH3:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][CH2:14][C:13]([CH3:17])([CH3:15])[CH2:12][O:11]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2cc(Cl)cc(Cl)c2)OC1
Yield: 80 %

Procedure:
The title compound (80%, crystals) was prepared from 3,5-dichlorophenylboronic acid and neopentylglycol.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]1)[N:5]=2.[F-].[Cs+].[OH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C(#N)C.O.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>[CH3:24][C@@H:19]1[O:20][C@H:21]([CH3:23])[CH2:22][N:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([C:32]4[CH:33]=[C:28]([OH:27])[CH:29]=[CH:30][CH:31]=4)[NH:3]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)[CH2:18]1
Reactant: OB(O)c1cccc(O)c1
Reactant: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(-c4cccc(O)c4)[nH]c3n2)C[C@H](C)O1
Temperature: 115 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a round bottom flask were added, 8-bromo-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (38.2 mg, 0.096 mmol), cesium fluoride 58.4 mg, 0.39 mmol), 3-hydroxyphenylboronic acid (39.8 mg, 0.29 mmol) and tetrakis(triphenylphosphine)palladium (8.9 mg, 7.69 mmol) followed by 1 mL of acetonitrile/water solvent mixture (10/1 ratio). Suspension was heated to 115° C. and stirred overnight. Upon completion of the reaction, the suspension was cooled and solids filtered off. Solvent was removed under reduced pressure and the crude was purified directly by preparative HPLC to provide 3-[2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purin-8-yl]-phenol (18.5 mg, 47%) as yellow solid. LC/MS analysis method 7, mass (ES+) m/z 411.2, retention time 1.40 min. 1HNMR (CDCl3): 7.34 (1H, d), 7.24 (2H, m), 6.87 (1H, d), 4.35 (2H, d), 4.30 (4H, brs), 3.80 (4H, m), 3.57 (2H, m), 2.53 (2H, t), 1.16 (6H, d).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].Br[CH2:9][CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:12][CH2:11][CH2:10][CH2:9][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7]
Reactant: O=C1CCC(=O)N1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCC(=O)N1CCCO
Yield: 32.8 %

Procedure:
A solution of pyrrolidine-2,5-dione (5 g, 50.5 mmol) and 3-bromopropan-1-ol (6.85 ml, 76 mmol) in acetonitrile (80 ml) containing potassium carbonate (14 g, 100 mmol) was refluxed overnight. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in methylene chloride and purified by column chromatography, eluting with ethylacetate/petroleum ether (4/1). After evaporation of the volatiles, the residue was distilled at 100-125° C. under about 0.1 mm Hg to give 1-(3-hydroxypropyl)pyrrolidin-2,5-dione (2.6 g, 34%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.[Br-].[CH2:21]([Zn+])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O1CCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCCC1>[CH2:21]([C:2]1[N:10]=[C:9]2[C:5]([N:6]([C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: Cn1c(=O)n(C(=O)N2CCCC2)c2cnc(Cc3ccccc3)nc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloro-9-methyl-7-(pyrrolidin-1-ylcarbonyl)-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 16> (200 mg), bis(tri-tert-butylphosphine)palladium (18 mg) and tetrahydrofuran (1.0 ml) was added dropwise 0.5 mol/L benzyl zinc bromide/tetrahydrofuran solution (2.14 ml) under nitrogen atmosphere and the mixture was stirred at 130° C. under microwave irradiation for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10). The obtained crude solids were recrystallized from a mixed solution of ethyl acetate and hexane to give the title compound 68 mg.
Reaction SMILES: C(C[C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[CH:10][C:9](=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)#N.[C:22]([OH:25])(=[O:24])[CH3:23].S(=O)(=O)(O)O>O>[O:21]=[C:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:23][C:22]([OH:25])=[O:24])[C:13]=2[O:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10]1
Reactant: N#CCc1cccc2c(=O)cc(-c3cccc(F)c3)oc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc2c(=O)cc(-c3cccc(F)c3)oc12

Procedure:
A mixture of 4.6 g of 8-cyanomethyl-2-(3-fluorophenyl)-4H-benzopyran-4-one; 18 ml of glacial acetic acid and 18 ml of sulfuric acid in 418 ml of water was stirred 12 hours at room temperature and diluted with 200 ml of water. The resulting suspension was filtered and the solids washed with water, then dissolved in 170 ml of 5% aqueous sodium bicarbonate, filtered to removed insoluble solids and acidified by addition of 11 ml of concentrated sulfuric acid. The resulting precipitate was filtered and the solids washed with water and dried to give 4.4 g of 4-oxo-2-(3-fluorophenyl)-4H-1-benzopyran-8-acetic acid as a white solid: IR 1645 and 1700 cm-1 ; m.p. 208°-211° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[O:22][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 88.3 %

Procedure:
A mixture of 29.4 g (0.200 mol) of 2-fluoro nitrobenzene, 41.0 g (0.200 mol) of 2-chloro-4-trifluoromethylphenol and 30.0 g (0.220 mol) of K2CO3 in 150 ml of DMSO was heated at 100° C. for six hours. The reaction mixture was poured over ice and extracted with ether. The organic phase was washed with water and saturated aqueous NaCl and dried (MgSO4). The solvent was removed by evaporation at reduced pressure to yield 56.1 g (88%) of the desired product as a yellow oil. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:23])[NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(O)C(N)(CO)CO>ClCCl.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)=[O:19])=[CH:21][CH:22]=2)=[O:23])[N:8]([CH3:10])[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)O)cc1
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid (0.08 g, 0.26 mmol) in a mixture of dichloromethane (4 mL) and DMF (0.20 mL) is added 1-(4-pyridinylmethyl)piperazine (0.046 g, 0.26 mmol), PS-DCC (0.41 g, 0.52 mmol) and HOBT (0.035 g, 0.26 mmol). The mixture is stirred overnight at 45° C. in a closed tube (orbital stirring). Then PS-Trisamine is added (0.52 mmol) and the mixture is stirred for 4 hr at room temperature, filtrated, and washed three times with dichloromethane. The solvents are evaporated under reduced pressure and the residue is purified by biotage column chromatography (eluent: ethyl acetate/methanol 10:1) to give 0.020 g (0.04 mmol), 16% as white solid. ES+(m/z)=476 [M+H].
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][C:24]1=O>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:30][CH2:31][C:32]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:28]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCc2ccccc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2ccccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 3,4-Dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6, 28.0, 28.3, 29.5, 30.5, 36.5, 36.6, 36.7, 37.5, 53.3, 53.6, 56.0, 59.1, 60.4, 60.8, 67.3, 104.7, 126.0, 126.1, 126.2, 128.8, 128.9, 129.5, 129.6, 131.1, 134.8, 135.3, 135.9, 136.3, 137.3, 172.6; MS m/z 438.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:27][CH:26]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made in the following manner: 2 g of 4-Bromobenzyl bromide and 1 equ. piperazine in acetonitrile would be stirred at room temperature and 1.1 g of potassium carbonate would be added. The reaction would be stirred at room temperature overnight. The solution would then be filtered through Celite and concentrated in vacuo to afford the crude product. Purification would be done by flash chromatography using a methylene chloride/methanol gradient.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([OH:7])=[O:6].[CH:13](O)=O>O>[CH3:12][N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: O=CO
Reactant: CNc1ccc(C(=O)O)cc1N
Solvent: O
Product: Cn1cnc2cc(C(=O)O)ccc21
Temperature: 85 °C
Yield: 84 %

Procedure:
To a stirred solution of 3-amino-4-(methylamino)benzoic acid (9 g, 1.0 eq) in 50 mL water, was added 50 mL formic acid and heated at 85° C. overnight. The mixture was cooled, concentrated in vacuo, and dissolved in water. Then 2N HCl was added to adjust pH to 1-3. The suspension was filtered and washed with water to give the product (9.7 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.37 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCNc1ccc([N+](=O)[O-])cc1

Procedure:
4.2 g (29.7 mmol) of N-tert.butoxycarbonyl-ethylenediamine, 5.0 g (31.2 mmol) of 4-fluoro-nitrobenzene and 7.0 g (50.6 mmol) of potassium carbonate are stirred in 25 ml of DMSO for 9 hours at 60° C. After cooling the mixture is diluted with water and extracted with ethyl acetate. The combined organic extracts are dried and evaporated down. The residue is stirred with petroleum ether, decanted off and evaporated down again. The product is stirred with ether and suction filtered.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([CH2:12][NH2:13])[CH:10]=[CH:11][C:2]1=2.[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:13][CH2:12][C:9]3[CH:10]=[CH:11][C:2]4[O:1][CH2:7][CH2:6][CH2:5][O:4][C:3]=4[CH:8]=3)=[O:25])[N:23]=2)[CH:20]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: NCc1ccc2c(c1)OCCCO2
Product: O=C(NCc1ccc2c(c1)OCCCO2)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: N#CCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a stirred solution of 3-(4-phenylpiperidin-1-yl)propionitrile (5.1 g, 24 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0M, 83 mL, 83 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 130 mL) was added and stirring was continued for 2 hours at 50-70° C. The mixture was basified to pH 9 by addition of 6N aq. NaOH and extracted with EtOAc (100 mL) and CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0M, 50 mL). The solvents were removed, ether (250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (60 mL) was added to the resulting white solid, the pH was adjusted to 10-11 with 1M NaOH, and the aqueous phase was extracted three times with CH2Cl2. Drying over MgSO4 followed by removal of solvents gave 4.5 g (87%) of pure product (light brown solid), which was characterized spectroscopically.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2c3c(nc4ccccc24)-c2ccccc2C3(c2ccccc2)c2ccccc2)cc1
Yield: 25.2 %

Procedure:
In all embodiment, the starting material 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol (385 mg, 2.50 mmol) and benzene (1430 mg, 18.31 mmol) are placed in a round bottom flask and then dissolved in 10 ml of dichloromethane. Subsequently, trifluoromethanesulfonic acid (0.09 ml, 1.10 mmol) is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 140° C., the crude product is extracted with 50 ml of Ethyl acetate and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 281 mg of 10,11,11-triphenyl-11H-indeno[1,2-b]quinoline. The percentage yield is 91.7%.
Reaction SMILES: [CH:1]1([O:32]P([O-])([O-])=O)[CH:6]([O:7]P([O-])([O-])=O)[CH:5]([O:12]P([O-])([O-])=O)[CH:4]([O:17]P([O-])([O-])=O)[CH:3]([O:22]P([O-])([O-])=O)[CH:2]1[O:27]P([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].N1C=CC=CC=1>O>[CH:6]1([OH:7])[CH:5]([OH:12])[CH:4]([OH:17])[CH:3]([OH:22])[CH:2]([OH:27])[CH:1]1[OH:32]
Reactant: O=P([O-])([O-])OC1C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C1OP(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 65 °C

Procedure:
Crystalline sodium phytate C (4 g) was dissolved with sonication in water (20 ml) and converted to the free acid by passage through a column of Dowex 50x8-200 ion-exchange resign. The column eluate was adjusted to pH 8 with pyridine and evaporated to dryness. The residue was dissolved in water (30 ml) and pyridine (130 ml) containing N,N-dicyclohexylcarbodiimide (8 g) was added. The reaction mixture was heated to 65° C. for 18 h and evaporated to dryness. The residue was extracted with water (4×10 ml) filtered and the filtrate was evaporated to dryness to give the pentapyridinium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (3.355 g, 77% yield). 31P-NMR (D2O) δ: −8.83 & −13.53 (AB, J=22.3 Hz, 2P, ax-eq), −9.82 & −10.00 (AB, J=17.8 Hz, 2P, eq-eq), −10.18 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 8.65 (d, J=5.6 Hz, 10H), 8.48 (dd, J=7.9, 7.9 Hz, 5H), 7.94 (dd, J=7.0, 7.0 Hz, 10H), 5.00 (bd, J=10.5 Hz, 1H), 4.57 (ddd, J=9.6, 9.6, 5.5 Hz, 1H), 4.43-4.36 (m, 2H), 4.30-4.18 (m, 2H); 13C-NMR (D2O) δ: 147.0, 140.9, 127.3, 77.9 (t, J=6.8 Hz), 76.4-76.0 (m), 75.4-75.0 (m), 73.8 (t, J=6.8 Hz), 73.3 (bs), 72.8 (bs). The compound was then dissolved in water (30 ml) and passed through a column Dowex 50Wx8 Na+ form. The column eluate was concentrated to dryness to give Hexasodium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (2.25 g, 97%) and used for biological experiments in 98.5% purity without any further purification. The impurity is unreacted starting material (or tripyrophosphate hydrolyzed back to starting material). 31P-NMR (D2O) δ: −8.34 & −13.14 (AB, J=21.7 Hz, 2P, ax-eq), −9.53 & −9.70 (AB, J=17.8 Hz, 2P, eq-eq), −9.92 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 5.04 (bd, J=10.5 Hz, 1H), 4.65-4.59 (m, 1H), 4.51-4.36 (m, 2H), 4.32-4.18 (m, 2H); 13C-NMR (D2O) δ: 77.1-76.8 (m), 76.5-76.0 (m), 75.4-75.0 (m), 74.1-73.9 (m), 73.7-73.2 (m), 73.2-72.5 (m).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+]>C(O)C>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C(=N)NC(=N)N
Yield: 76.9 %

Procedure:
20.00 g (1 equivalent) of metformin hydrochloride and 4.84 g (1 equivalent) of sodium hydroxide were stirred in 200 Ml of ethanol for 2 hours at room temperature, and then remaining solid was filtered and the filtrate was concentrated under reduced pressure. Then 300 Ml of acetone was added to the resulting solid and stirred. Insoluble material was filtered, and the filtrate was concentrated under reduced pressure to obtain 12.0 g of metformin free base. 500 Ml of acetone and 10 Ml (1.45 equivalents) of glacial acetic acid were added to the metformin free base, and then the mixture was stirred. The resulting crystal was filtered and washed with acetone, and then dried at 60° C. to obtain 13.6 g of metformin acetate (yield: 59.5%).