Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[CH:9]1([CH2:14][CH:15]([C:24]2[CH:25]=[N:26][C:27]([SH:30])=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1>CN(C=O)C>[CH:9]1([CH2:14][CH:15]([C:24]2[CH:25]=[N:26][C:27]([S:30][CH3:3])=[CH:28][CH:29]=2)[C:16]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(S)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 16 h

Procedure:
MeI (44 μL of a 2.3M solution in anhydrous DMF, 102 μmol) and K2CO3 (14 mg, 102 μmol) were added to a stirred solution of 3-cyclopentyl-2-(6-mercaptopyridin-3-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 66, 34 mg, 102 μmol) in anhydrous DMF (1 mL). After 16 h, the solvents were evaporated off under reduced pressure, then the residue was partitioned between EtOAc (12 mL) and H2O (5 mL). The organic layer was washed with H2O (5 mL) and brine (5 mL), before being dried (MgSO4). The solution was filtered, passed through a short SiO2 plug, and evaporated to give 3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=348.2 [M+H]+. Step 2: Oxidation of this thioether (52 mg, 150 μmol), by the protocol described in EXAMPLE 55, gave the title compound: RTA=3.17 min; m/z (ES+)=364.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[N:2]1.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][NH:1]2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ncc23)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
100 mg (0.75 mmol) of 1H-indazol-4-ol (from example XXIV), 94 mg (0.64 mmol) of 3,4-difluoronitrobenzene and 103 mg (0.75 mmol) of potassium carbonate are suspended in 2 ml of anhydrous dimethylformamide, and the mixture is stirred at 50° C. for 5 hours. The reaction solution is then diluted with water and extracted 2× with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude product is purified by preparative HPLC.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1C(=O)NC(=O)N([C@@H:19]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])C=1>P([O-])([O-])([O-])=O.O>[CH:2]1[N:3]=[C:4]2[N:5]([C@@H:19]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]3[OH:27])[CH:6]=[N:7][C:8]2=[C:9]([NH2:10])[N:1]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 51.3 %

Procedure:
50 kg of wet cell paste obtained by fermenting E. aerogenes were resuspended in approximately 200 liters of 30 mM phosphate buffer at pH 7 and mixed with 800 liters of phosphate buffer in which had been dissolved at elevated temperature 5.4 kg of adenine (final concentration 40 mM) and 8.9 kg of Ara-U (final concentration 40 mM). The mixture was maintained at 60° C., with agitation, for 20 hours, diluted to approximately 3000 liters with hot H2O and subjected to diafiltration on a membrane, collecting approximately 5000 liters of ultrafiltrate. The bioconversion yield determined by RP-HPLC was approximately 55%. The residue containing the cell paste is used for a subsequent reaction. The ultrafiltrate was concentrated to approximately 1000 liters and cooled to collect the precipitate constituted by Ara-A contaminated with non-reacted adenine (approximately 30 g of adenine per 100 g of Ara-A). 5 kg of Ara-A (total yield approximately 46%) with a degree of purity higher than 99.5% were finally obtained after crystallisation with H2O.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:13][CH3:14])(=[O:12])[CH2:7][CH2:8][C:9]([CH3:11])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:14][O:13][C:6](=[O:12])[CH2:7][CH2:8][CH:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:11]
Reactant: COC(=O)CCC(C)=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC(C)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Pyrrolidine (3 mL, 36 mmol, 1.2 eq) was dissolved in DCM (50 mL) and methyl levulinate (4 mL, 30 mmol, 1.0 eq) was added. The solution was stirred at room temperature for 1 hour, then Na(OAc)3BH (7.6 g, 36.0 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 16 hours, then brine was added, the crude was extracted with DCM and dried. 2.0 g of the title product were obtained (34% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18](Br)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1Br)OCCN(Cc1ccccc1)C2
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc2c(c1-c1ccoc1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
A mixture of 4-benzyl-9-bromo-8-fluoro-2,3,4,5-tetrahydro-1,4-benzoxazepine (500 mg, 1.49 mmol), 3-furanboronic acid (250 mg, 2.23 mmol), potassium carbonate (206 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (172 mg, 0.149 mmol), 1,2-dimethoxyethane (5 ml) and water (0.5 ml) was stirred under an argon atmosphere at 100° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and preparative HPLC to give the desired product (104 mg, 21.7%) as an oil.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O.O.Cl>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: CCC/C=C/C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of t-BuOK (1 g, 8.9 mmol) in DMSO (15 mL) at rt, was added compound cyanoacetamide (0.824 g, 9.8 mmol) and (E)-hept-3-en-2-one (1 g, 8.91 mmol). Reaction mixture was stirred for 30 min at rt. Additional t-BuOK (3 g, 26.7 mmol) was added and reaction was stirred at rt in presence of air. On completion, it was diluted with H2O and slowly by 4N HCl. Precipitated solid was filtered, washed with water and dried. Crude product was triturated with ether to afford the title compound (0.5 g, 33%).
Reaction SMILES: CC1(C)[O:6][C@H:5]2[C@H:7]([NH:12][C:13]3[N:18]4[N:19]=[C:20]([C:22]5[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH:25]=[CH:24][CH:23]=5)[CH:21]=[C:17]4[N:16]=[CH:15][CH:14]=3)[CH2:8][C@H:9]([CH2:10][OH:11])[C@H:4]2[O:3]1.Cl[S:34]([NH2:37])(=[O:36])=[O:35].Cl.O>CN(C)C=O>[S:34](=[O:36])(=[O:35])([O:3][CH2:4][C@H:9]1[CH2:8][C@@H:7]([NH:12][C:13]2[N:18]3[N:19]=[C:20]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[CH:21]=[C:17]3[N:16]=[CH:15][CH:14]=2)[C@H:5]([OH:6])[C@@H:10]1[OH:11])[NH2:37]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3ccnc4cc(-c5cccc6ccccc56)nn34)[C@@H]2O1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2ccnc3cc(-c4cccc5ccccc45)nn23)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
To a vial charged with (s.e.)-((3aR,4R,6R,6aS)-2,2-dimethyl-6-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (1.76 g, 4.09 mmol) in N,N-dimethylformamide (7.20 mL) is added chlorosulfonamide (1.42 g, 12.3 mmol; obtained by the method described in J. Am. Chem. Soc. 2005, 127, 15391). After 1 hr, the reaction is quenched with methanol (5 mL). 6.0 M hydrochloric acid in water (3.41 mL, 20.4 mmol) is added and the mixture is stirred for 1 hr. Solvent is removed in vacuo and the crude material is purified by preparative HPLC to provide (s.e.)-((1R,2R,3S,4R)-2,3-dihydroxy-4-{[2-(1-naphthyl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}cyclopentyl)methyl sulfamate. LCMS: (AA) M+1 470; 1H NMR (400 MHz, MeOD) δ 8.48-8.40 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 7.99-7.90 (m, 2H), 7.81-7.75 (m, 1H), 7.60-7.47 (m, 3H), 6.69 (s, 1H), 6.37 (d, J=5.6 Hz, 1H), 4.24-4.06 (m, 3H), 4.04-3.99 (m, 1H), 3.96-3.89 (m, 1H), 2.55-2.45 (m, 1H), 2.45-2.35 (m, 1H), 1.60-1.48 (m, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.FC(F)(F)C1N=CC(=O)NC=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:30]>OS(O)(=O)=O>[Cl:30][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: Nc1cnc(C(F)(F)F)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=c1cnc(C(F)(F)F)c[nH]1
Product: FC(F)(F)c1cnc(Cl)cn1

Procedure:
2-Amino-5-trifluoromethylpyrazine (Miesel, U.S. Pat. No. 4,293,552) was converted into 5-trifluoromethylpyrazin-2-one (Fitzjohn, EP 408196). 5-Trifluoromethylpyrazin-2-one (0.5 g) was heated at reflux in POCl3 (3 ml) containing 1 drop of conc. H2SO4 for 3 h. The cooled mixture was poured onto ice and brought to pH 5 by addition of solid NaHCO3 and extracted (3×) with diethyl ether. The ethereal extracts were washed with water and brine, dried (Na2SO4) and evaporated to give the title compound (D31) as a light yellow oil (0.2 g) which was sufficiently pure for use without further purification. 1H NMR δ [CDCl3]: 8.72 (1H, s), 8.76 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)c1cccn1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Nc1ccc(OC)cc1)c1cccn1C
Yield: 58 %

Procedure:
To a solution of 4.0 g ethyl 1-methylpyrrole-2-glyoxylate and 2.96 g p-anisidine in 20 ml toluene is added 24 mg p-toluenesulfonic acid. Heating at reflux for 4 days with water being removed with a Dean-Stark trap is followed by washing successively with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. After drying, evaporation of the solvent affords a dark solid. Recrystallization from isopropanol gives a 58% yield of ethyl α-(4-methoxyphenylimino)-1-methylpyrrole-2-acetate, m.p. 83°-85° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9](O[C@@H](C)CC)=[N:10][C:11]=2[NH2:17].FC(F)(F)C(O)=O.[CH3:30][C@H:31]([NH:35]C1NC2C(N=C(OC)N=2)=C(N)N=1)[CH2:32][CH2:33][CH3:34].BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:35][C@@H:31]([CH3:30])[CH2:32][CH2:33][CH3:34])=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: CCC[C@H](C)Nc1nc(N)c2nc(OC)nc-2[nH]1
Agent: ClCCCCBr
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Nc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from N2-[(1S)-1-methylbutyl]-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.C(N)(=O)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(O[C@@H:32]1[O:49][CH2:48][C@@H:43]([O:44][C:45](=[O:47])[CH3:46])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:33]1[O:34][C:35](=[O:37])[CH3:36])(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]([C@@H:48]3[O:49][CH2:32][C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@@H:38]([O:39][C:40](=[O:42])[CH3:41])[C@H:43]3[O:44][C:45](=[O:47])[CH3:46])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc2nc[nH]c2cc1Cl
Agent: CC(N)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(Cl)c(C)cc21
Temperature: 25 °C

Procedure:
As described in General Procedure III, 5-chloro-6methylbenzimidazole (1.0 g, 6 mmol), N,O-bis(trimethylsiyl) acetamide (Aldrich, 1.3 ml, 5.2 mmol), and 1,2-dichloroethane (Aldrich Sure Seal, 300 mL) were combined and refluxed under nitrogen for 0.5 h. The solution was cooled to room temperature and trimethylsilyl triflate (Aldrich, 1.3 ml, 6.7 mmol) was added. Immediately, 2.0 g (6.3 mmol) solid 1,2,3,4-tetra-O-acetyl-b-D-ribopyranose (beta-D-ribopyranose 1,2,3,4-tetraacetate, Aldrich, Milwaukee) was added. The solution was stirred under nitrogen at reflux overnight, then poured into 7% aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (5×20 cm, 230-400 mesh) eluting with a step gradient of 0.25 to 2.5% methanol in chloroform to give 0.07 g (0.16 mmol) 5-Chloro-6-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole; MS (AP+): m/z (rel. intensity) 447 (1.0, M+23 (Na)) 1H NMR (DMSO-d6) δ8.36 (s,1H), 7.90 (s, 1H), 7.68 (s, 1H), 5.97-5.95 (d, 1H, J=9.1 Hz), 5.72-5.69 (m, 2H), 5.41-5.40 (m, 1H), 4.02-3.92 (m, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 1.98 (s, 3H), 1.69 (s, 3H) and 0.090 g (0.21 mmol) 6-Chloro-5-methyl-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole 1H NMR (DMSO-d6) δ8.36 (s,1H), 8.06 (s, 1H), 7.60 (s, 1H), 5.99-5.96 (d, 1H, J=9.6 Hz), 5.73-5.66 (m, 2H), 5.45-5.40 (m, 1H), 4.02-3.92 (m, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.98 (s, 3H), 1.69 (s, 3H) and 0.13 g (0.31 mmol) of a mixture of the two regioisomers (11% total yield).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][C:19](OCC)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO.O>C1(C)C=CC=CC=1.ClCCl>[C:24]1([CH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][CH2:19][OH:20])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: OCCC(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 100.2 %

Procedure:
To a 30 L reaction kettle was slowly added a solution of diisobutylaluminum hydride in toluene (15 L, 1 mol/L) at −20° C. After stirring, to the resulting mixture was slowly added a solution of ethyl 3,3-diphenyl-1-propanate (1200 g, 4.7 mol) in dichloromethane dropwisely. After the completion of dropwise addition, the reaction was conducted at 25° C. for 12 hours. After the completion of reaction monitored by TLC, the reaction solution was divided into three parts. 200 mL methanol and 1000 mL water were slowly added respectively at −20° C. to quench off the reaction. The reaction solutions were combined and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, and evaporated to remove the solvent to produce an oily crude product of 3,3-diphenyl-1-propanol (1000 g), which was directly used in the next reaction.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[C:20]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:19]2=[N:18][C:17]=3[NH2:28])=[C:9]([CH3:31])[CH:8]=1.[P:35](OCC)([O:40]CC)([O:37]CC)=[O:36].C[Si](Br)(C)C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:28][C:17]1[C:16]2[N:15]=[CH:14][C:13]([CH2:12][CH2:11][C:10]3[CH:29]=[CH:30][C:7]([O:6][CH2:5][C:4]4[CH:3]=[C:2]([P:35](=[O:36])([OH:40])[OH:37])[CH:34]=[CH:33][CH:32]=4)=[CH:8][C:9]=3[CH3:31])=[CH:22][C:21]=2[C:20]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:19]=2[N:18]=1
Reactant: CCOP(=O)(OCC)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4cccc(I)c4)cc3C)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCc4cccc(P(=O)(O)O)c4)cc3C)cc12
Temperature: 90 °C

Procedure:
To a stirred solution of 2-(4-(3-iodobenzyloxy)-2-methylphenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (1.0 equiv.) in triethyl phosphate (1.05 eq.) was added palladium acetate (0.08 eq.). The resulting reaction mixture was heated at 90° C. overnight. After the reaction was cooled down to room temperature, the residue was taken up in DCM (0.27 M) at 0° C., and was treated with TMSBr (11 equiv.). The reaction was warmed to room temperature over 2 hours, and then quenched with small amounts of MeOH. The DCM was removed by evaporation, and then added DMSO/water. The mixture was adjusted to pH 9 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo to give 3-((4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)methyl)phenylphosphonic acid (13) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 8.84 (s, 1H), 8.72 (s, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.67 (d, 1H, J=12 Hz), 7.60-7.54 (m, 1H), 7.30-7.20 (m, 2H), 7.15 (d, 1H, J=8.4 Hz), 7.11 (d, 1 H, J=8.4 Hz), 7.04 (s, 1H), 6.84 (s, 1H), 6.77 (m, 1H), 4.99 (s, 2H), 3.12-2.92 (m, 4H), 2.44 (s, 3 H), 2.27 (s, 3H). LRMS [M+H]=514.2
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[NH2:12][C:13]1[C:18](Cl)=[N:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[NH2:12][C:13]1[C:18]([O:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH3:1])=[N:17][CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccnc1Cl
Reactant: Cc1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1nccnc1N
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
To a solution of 2-methylbenzyl alcohol (0.985 g) in N,N-dimethylformamide (10 ml) was added 62.8% sodium hydride (0.308 g) under a nitrogen atmosphere and then stirred for 30 minutes. 2-Amino-3-chloropyrazine (0.87 g) was added to the solution and the mixture was heated at 65° C. for 2 hours and poured onto crushed ice. The resulting precipitates were collected by filtration, washed with n-hexane, and dried in a desiccator to give 2-amino-3-(2-methylbenzyloxy)pyrazine (0.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.S(O[Si](C)(C)C)(O[Si](C)(C)C)(=O)=O>ClCCl>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Reactant: C1=COCCC1
Agent: C[Si](C)(C)OS(=O)(=O)O[Si](C)(C)C
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.0 g of trans-4-(4'-cyano-4biphenylyl)cyclohexanol. 1.1 ml of 3,4-dihydro-2H-pyran in 30 ml of dichloromethane was treated at 0° C. with a solution of 0.007 g of bistrimethylsilyl sulfate in 2 ml of dichloromethane. The reaction mixture was stirred at 0° C. for a further 30 minutes and then washed once with sodium carbonate solution and twice with water and subsequently dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel with toluene/ethyl acetate (vol. 9;1). Recrystallization from ethyl acetate at -20° C. gave 1.75 g of pure trans-4-(4'-cyano-4-biphenylyl)cyclohexyl tetrahydropyranyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][OH:26])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(C)c1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccnc(CO)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
3-Benzyloxy-4-methoxy-2-methylpyridine (23.0 g) was dissolved in 200 ml of dichloromethane. m-Chloroperbenzoic acid (20.7 g) was added to the solution under ice cooling, and a reaction was allowed to proceed at room temperature overnight. The reaction product was washed with an aqueous saturated sodium hydrogensulfite solution and an aqueous saturated sodium hydrogencarbonate solution, and the washed reaction product was dried over anhydrous sodium sulfate. The solvent was concentrated under the reduced pressure. Acetic anhydride (200 ml) was added to 35.5 g of the concentrate as a light yellow oil, and a reaction was allowed to proceed at 100° C. for one hr. Ethanol (100 ml) was then added thereto, and the mixture was further refluxed for one hr. The reaction solution was concentrated under the reduced pressure. A 2 M solution (200 ml) of sodium hydroxide in 50% methanol was added to the concentrate, and the mixture was stirred at 80° C. for one hr. The reaction solution was concentrated under the reduced pressure. The concentrate was extracted with chloroform. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate, followed by concentration under the reduced pressure to give 19.6 g (yield 80%) of 3-benzyloxy-2-hydroxymethyl-4-methoxypyridine as a yellowish brown solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[N:15]1([C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: NCC(=O)N(CC(=O)N1CCc2ccccc21)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCc3ccccc32)c2ccccc2)c1
Yield: 27.2 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.8 g of 2-amino-N-[2-(1-indolinyl)-2-oxoethyl]-N-phenylacetamide and 0.8 g of 3-methylphenyl isocyanate are used as the starting material. After recrystallization from a mixture of ethyl acetate and dimethylformamide (80-20 by volume), 0.7 g of N-[2-(1-indolinyl)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 190° C. is obtained.