Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:38]=[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([S:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[N:23][N:22]=4)=[CH:16][CH:15]=3)[N:7]2[N:6]=1)C=C.C([O-])=O.[NH4+]>CO.[Pd].CCOC(C)=O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([S:13][C:12]4[N:7]5[N:6]=[C:5]([OH:4])[CH:38]=[C:8]5[N:9]=[CH:10][CH:11]=4)=[CH:19][CH:18]=3)=[N:22][N:23]=2)=[CH:32][CH:33]=1
Reactant: C=CCOc1cc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)n2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)n2n1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(4-(2-(allyloxy)pyrazolo[1,5-a]pyrimidin-7-ylthio)phenyl)-4-(4-chlorophenyl)phthalazin-1-amine (0.110 g, 0.20 mmol, Example 4) and ammonium formate (130 mg, 2.0 mmol) in MeOH (7 mL) was added a slurry of 10% palladium on carbon, (44 mg) in EtOAc (1 mL). The mixture was heated to 65° C. After 8 hrs, the mixture was cooled to RT, filtered over celite, concentrated in vacuo, and purified by silica gel chromatography using 5-15% MeOH in CH2Cl2 with 1% NH4OH to afford 7-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)pyrazolo[1,5-a]pyrimidin-2-ol as a light yellow solid. MS: Found M+H+=497.0.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:18][C:12]2=[N:13][CH:14]=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]Cl.[Cl-].[Na+]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:1]([S:8][C:9]1[S:18][C:12]2=[N:13][CH:14]=[C:15]([I:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClI
Reactant: O=c1ccnc2sc(SCc3ccccc3)nn12
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=c1c(I)cnc2sc(SCc3ccccc3)nn12
Reaction time: 1 h
Yield: 18 %

Procedure:
Five (5) grams of the thus obtained 2-benzylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 5 g of zinc chloride were added to 50 ml of acetic acid. Six (6) grams of iodine monochloride was added to the mixture, and the mixture was stirred at 70°-80° C. for 1 hour. After the reaction was finished, the reaction mixture was cooled and a sodium chloride solution was added. The deposited crystals were collected by filtration, washed with water and isopropyl ether and thus 1.3 g of 2-benzylthio-6-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 18%.
Reaction SMILES: C([Li])(CC)C.[C:6]([Si:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].B(OC)(OC)[O:23]C.CC(O)=O.OO>C1COCC1.C(OCC)C>[Si:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([OH:23])[CH:16]=1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:12])[CH3:11]
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(F)cc1
Agent: OO
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)c(O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
sec-Butyllithium (20.7 mL, 29.0 mmol) was added dropwise to a solution of tert-butyl(4-fluorobenzyloxy)dimethylsilane (2) (6.33 g, 26.3 mmol) in THF (30 mL) over 30 min, at −78° C. Trimethyl borate (2.99 mL, 26.3 mmol) was added dropwise over 30 min while the temperature was maintained at −78° C. The reaction mixture was allowed to warm to 0° C. and AcOH (2.26 mL, 39.5 mmol) was added dropwise, followed by hydrogen peroxide (2.48 mL, 29.0 mmol). The mixture was stirred at 0° C. for 30 min then allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with diethyl ether (100 mL) and washed with 2M NaOH (100 mL) and brine (100 mL). The organic solution was dried over MgSO4, filtered and the solvent was removed in vacuo to give 5-((tert-butyldimethylsilyloxy)methyl)-2-fluorophenol (3) (4.0 g, 50%) as a colourless oil: m/z 255 [M−H]− (ES−).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH2:26])[CH:22]=[N:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1(C)C=CC=CC=1>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([NH:26][C:29](=[O:31])[CH3:30])[CH:22]=[N:21]4)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2n1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-quinoxalin-2-ylamine, (Example 37(d)), (0.55 g, 1.4 mmol) and acetic anhydride (0.82 mL, 8.6 mmol, Aldrich) in toluene (15 mL) was heated at 75° C. for 4 h. After stirring at room temperature for 16 h the mixture was treated with hexanes. The solids were removed by filtration, washed with hexanes and dried in vacuum for 24 h at room temperature to give the title compound as a tan powder. Mp: 237° C., MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:3].[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:16]=[C:14]([CH:13]=[CH:12][C:9]2[CH:8]=[CH:7][C:6]([S:5][C:2]([F:4])([F:3])[F:1])=[CH:11][CH:10]=2)[O:15][CH:20]=1
Reactant: NC(=O)C=Cc1ccc(SC(F)(F)F)cc1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.45 g (18.0 mmol) 3-(4-trifluoromethylsulfanyl-phenyl)-acrylamide, 2.79 g (22.0 mmol) dichloro acetone and 50.0 ml toluene were kept at reflux temperature for 30 h with continuous removal of water by use of a Dean-Stark trap (a water separator used in chemical reactions). The reaction mixture was cooled for 30 min. in an ice bath and the precipitated amide (1.2 g) was removed by filtration and discarded. After removal of solvents in vacuo, the residue (5.92 g) was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 1:1). All fractions containing the product were concentrated to a volume of 10 ml, n-heptane added and the crystallized material isolated by filtration, washed with cold heptane and dried. 2.02 g (35%) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]#[C:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1>CN(C=O)C.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)[N:18]=1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (0.050 g) and tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A60) (0.200 g, 0.302 mmol) in DMF (10 mL) and Et3N (1 mL) was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The resulting mixture was filtered through Celite, washing with MeOH. The volatiles were removed under reduced pressure then the residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.; repeated twice) to give the title compound A61 (170 mg, 84%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.49 (s, 1H), 7.47-7.45 (m, 1H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 4.37-4.17 (m, 2H), 3.79 (s, 2H), 3.69 (s, 3H), 3.24-3.14 (m, 2H), 3.21-3.06 (m, 2H), 2.92-2.72 (m, 2H), 2.71-2.52 (m, 1H), 1.90-1.74 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 9H). LCMS-A: rt 7.149 min; m/z 667 [M+H]+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2([C:36]([N:38]3[CH2:42][CH2:41][C:40](=[O:43])[CH2:39]3)=[O:37])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(O)(=O)C.C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2([C:36]([N:38]3[CH2:42][CH2:41][C:40]([CH2:16][C:17]4[N:25]=[CH:24][CH:23]=[CH:22][C:18]=4[C:19]([OH:21])=[O:20])([OH:43])[CH2:39]3)=[O:37])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1cccnc1CC1(O)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: -45 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethyl-piperidine (0.123 g, 0.000872 mol) in tetrahydrofuran (3.00 mL, 0.0370 mol) at −75° C. was added 2.50 M of n-butyllithium in hexane (0.500 mL). After stirring for 15 min., a suspension of 2-methylnicotinic acid (120.5 mg, 0.0008787 mol) in THF (5.0 mL) was added at −55° C. The mixture was stirred at −55° C. for 1 h. 1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (100.0 mg, 0.0003792 mol, prepared in steps 1 and 2 of example 288) was added to the above mixture and the reaction temperature was maintained at −50 to −40° C. The mixture was stirred at −40° C. for 30 minutes, then slowly warmed up to 0° C. To the mixture was added acetic acid (0.50 mL, 0.0088 mol) at 0° C. and the reaction mixture was stirred overnight while gradually warming to rt. The reaction mixture was carefully neutralized with NaHCO3 and the resulting mixture was extracted with AcOEt (4×30 mL). The combined organic layer was washed with brine (30 mL), dried over MgSO4, and concentrated. The residue was purified by Combiflash with ethyl acetate/heaxane to give the desired product. LC/MS (M+H+) 401.7.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=CC(O)=CC=1)C.C1(O)C=CC=CC=1.C1C(O)=CC=C(C)C=1.C(O)(=O)C(O)=O>O>[CH:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C=Cc1ccc(O)cc1
Agent: CCc1ccc(O)cc1
Agent: Cc1ccc(O)cc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: Oc1ccccc1
Product: C#Cc1ccc(O)cc1
Temperature: 180 °C

Procedure:
409.8 g of a mixture consisting of 21.4% of p-vinylphenol, 59.8% of p-ethylphenol, 1.5% of phenol, 7.7% of p-cresol and 9.6% of water was introduced, over 30 minutes, into a rotary evaporator heated at 180° C. under a vacuum of 6 mmHg, and vacuum flash distillation was conducted. 364.2 g of a distillate was obtained and its composition was 21.3% of p-vinylphenol, 61.6% of p-ethylphenol, 1.5% of phenol, 7.8% of p-cresol and 7.8% of water. 132.4 g of this p-vinylphenol fraction was mixed, without being dehydrated, with 0.12 ml of a 0.5 M aqueous oxalic acid solution. The -resulting mixture was polymerized at 45° C. for 6 hours. The reaction mixture was treated in the same manner as in Example 1 to obtain 26.2 of a poly(p-vinylphenol). The polymer had a Mw of 10,470, Mn of 7,180, a light transmittance at 248 nm, of 70.5% and glass transition temperature of 173° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:29])[N:4]([CH2:24][CH2:25][C:26]([OH:28])=O)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH:6]=2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:52]([CH2:54][NH2:55])[OH:53]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:53][CH2:52][CH2:54][NH:55][C:26](=[O:28])[CH2:25][CH2:24][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:6]=2)[N:11]=[C:2]([CH3:1])[C:3]1=[O:29]
Reactant: NCCO
Reactant: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCC(=O)O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(NCc3cccc(C(F)(F)F)c3)cc2n(CCC(=O)NCCO)c1=O
Reaction time: 8 h

Procedure:
In this example 3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)-quinoxalin-I (2H)-yl)propanoic acid (50 mg) was dissolved in chloroform (1 mL). HOBt (20 mg), EDC hydrochloride (29 mg), triethylamine (75 μL), and ethanolamine (9 μL) were added sequentially to the reaction flask and stirred overnight. Concentrated and residue chromatographed on silica gel using 5% MeOH in dichloromethane as eluent. Product N-(2-hydroxyethyl)-3-(3-methyl-2-oxo-7-(3-(trifluoromethyl)benzylamino)-quinoxalin-1(2H)-yl)propanamide is isolated as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:18])[N:10]([CH3:19])[C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(F)cc2)c1=O
Temperature: 100 °C
Reaction time: 36 h
Yield: 69.1 %

Procedure:
First, 0.659 g of 3-(4-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1001) was dissolved in 3.8 ml of N,N-dimethylformamide, to which 0.529 g of potassium carbonate and 0.32 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 1.5 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=8:1), which afforded 0.480 g (yield, 69%) of 3-(4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-4; m.p., 121.1° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])[C:11]=1[CH:12]=O.CC1C=CC=C(N)C=1C=O.ClC(OC)=O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([N:8]=[CH:12][C:11]2[C:14]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=[CH:17][C:10]=2[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1N
Reactant: COC(=O)Nc1cccc(C)c1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COC(=O)Cl
Agent: Cc1cccc(N)c1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Nc1cccc(C)c1C=Nc1cccnc1N
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a solution of 2,3-diaminopyridine (546 mg) and 2-methyl-6-methoxycarbonylaminobenzaldehyde (966 mg)*, which was prepared by reacting 2-methyl-6-aminobenzaldehyde with methyl chloroformate according to a similar manner to that of Preparation 2, and triethylamine (2.5 g) in methylene chloride (26 ml) was added a 0.5M solution of titanium tetrachloride in methylene chloride (6 ml) at 0° C. and the mixture was stirred for 2 hours at the same temperature. To the mixture, water was added and the insoluble materials were removed by filtration, and the organic layer was separated. The solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (27 g), eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired product were combined and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give 2-amino-3-(2-methyl-6-methoxycarbonylaminobenzylideneamino)pyridine (279 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[C:21]([Cl:26])[N:20]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[C:23]([NH:25][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)[CH:22]=[C:21]([Cl:26])[N:20]=1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3cc(Cl)nc(Cl)c3)n2)c1
Yield: 7.8 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 2,6-dichloropyridin-4-amine (57.1 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as for Method L followed by preparative TLC afforded 7 mg of title compound. Yield: 7.8%. 1H NMR (250 MHz, DMSO-d6) δ 2.08 (s, 3 H), 7.48 (t, 1 H, 7.9 Hz), 7.65 (d, 1 H, 8.0 Hz), 7.71 (d, 1 H, 7.6 Hz), 7.85 (s, 2 H), 8.30 (s, 1 H), 8.32 (bs, 1 H), 8.66 (s, 1 H), 10.10 (s, 1 H), 10.55 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 23.9, 110.3, 117.47, 120.6, 121.2, 129.4, 133.4, 134.2, 136.3, 140.0, 148.3, 149.5, 149.7, 151.4, 168.3; m/z 374.1 [(M+H)+, calcd for C17H13Cl2N5O 373.0].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:35])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [Br-].[C:2]1([I+:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:31])([F:30])[C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[S:20]([OH:23])(=[O:22])=[O:21]>[Ag]=O.CO>[F:31][C:16]([F:15])([F:30])[C:17]([F:28])([F:29])[C:18]([F:26])([F:27])[C:19]([F:24])([F:25])[S:20]([O-:23])(=[O:22])=[O:21].[C:9]1([I+:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=[Ag]
Agent: [Br-]
Agent: c1ccc([I+]c2ccccc2)cc1
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To 100 ml of methanol, 3.61 g (0.01 mole) of diphenyliodonium bromide and 1.62 g (0.007 mole) of silver oxide were suspended, then the mixture was reacted at room temperature for 2 hours. To the reaction solution, 4.2 g (0.014 mole) of nonafluorobutanesulfonic acid was added drop-wise at room temperature, followed by reacting at the same temperature for 2 hours while stirring. The thus obtained reaction mixture was filtered and concentrated under reduced pressure, followed by purifying 6.4 g of the residue by column chromatography [Wako gel, C-200; eluent of methylene chloride/methanol=9/1 (v/v)], to obtain 4.6 g of diphenyliodonium nonafluorobutanesulfonate as a colorless crystal. The thus obtained crystal was named acid generator B1. The measurement results of melting point and NMR of acid generator B1 are shown bellow.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:16])[C:10](=[O:14])[NH:9]2)=[CH:6][C:7]=1[F:8]
Reactant: O=C(C=NO)Nc1ccc(F)c(Br)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Br)c(F)cc2C1=O
Temperature: 90 °C
Yield: 80 %

Procedure:
To concentrated sulfuric acid (40 mL) at 50° C. was added N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide (4 g, 0.0152 mol). The temperature was raised to 90° C. and maintained for 3 hours. The reaction mixture was added to ice cold water to provide a precipitate. The precipitate was filtered and dried to provide the title compound (3.0 g, 80%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[Br:9][C:10]1[CH:11]=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([O:22][CH3:23])=[C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([N:19]1[CH2:18][CH2:17][N:16]([C:14]2[CH:15]=[C:10]([Br:9])[CH:11]=[C:12]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:13]=2[O:22][CH3:23])[CH2:21][CH2:20]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(N2CCNCC2)cc(Br)cc1C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N2CCN(C(=O)COC(C)=O)CC2)cc(Br)cc1C(C)(C)C
Reaction time: 1 h

Procedure:
Acetoxyacetyl chloride (0.14 ml) was added to a solution of 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazine (360 mg) and triethylamine (0.31 ml) in CH2Cl2 (5 ml) while cooling on ice and the mixture was brought to room temperature and stirred for 1 hour. After quenching the reaction with brine, extraction was performed with ethyl acetate to yield a crude product of 2-{4-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]piperazino}-2-oxoethyl acetate as a red oil. This crude product was dissolved in methanol (2.5 ml) and potassium carbonate (167 mg) was added. After 15 minutes, brine was added, extraction was performed with ethyl acetate, the extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (285 mg) as light orange crystals (67%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][N:18]=2)[N:13]=[CH:12][C:11]=1[NH2:20])[CH2:2][CH2:3][CH3:4].[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][N:9]1[C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:21]1[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Cl
Reactant: CCCCOCCCNc1c(N)cnc2cccnc12
Product: CCCCOCCCn1c(CCCC)nc2cnc3cccnc3c21
Yield: 63.1 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) was reacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resulting amide intermediate was cyclized to provide 2.9 g of 1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine as a colorless oil. A small portion was purified by flash chromatography (silica gel eluting with ethyl acetate) to provide a pure sample as a white powder, m.p. 56.5-57.5° C. Analysis: Calculated for C20H28N4O: % C, 70.56; % H, 8.29; % N, 16.46; Found: % C, 70.48; % H, 8.25; % N, 16.61. 1H NMR (300 MHz, CDCl3): δ 9.32 (s, 1H), 8.90 (dd, J=4.3, 1.6 Hz, 1H), 8.49 (dd, J=8.5, 1.6 Hz, 1H), 7.57 (dd, J=8.5, 4.3 Hz, 1H), 4.94 (t, J=7.0 Hz, 2H), 3.45-3.39 (m, 4H), 3.04 (t, J=7.9 Hz, 2H), 2.26 (pentet, J=6.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.62-1.48 (m, 4H), 1.45-1.33 (m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).