Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH2:12][NH2:13]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:12][NH2:13]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: NN
Solvent: CC(C)O
Product: NNc1ccc([N+](=O)[O-])cc1F

Procedure:
From the reaction of 3,4-difluoronitrobenzene with hydrazine in isopropyl alcohol at an elevated temperature (e.g. 75°-85° C.) there is produced 2-fluoro-4-nitrophenylhydrazine. The latter is then treated with acetone and sulfuric acid in tetrahydrofuran to yield N'-(2-fluoro-4-nitrophenyl)-dimethylketone hydrazone. The latter is then treated with potassium cyanate in aqueous acetic acid to produce 1-(2-fluoro-4-nitrophenyl)-5,5-dimethyl-1,2,4-triazolidin-3-one. The latter is then reacted with pyruvic acid and sulfuric acid in 1,4-dioxane to form 2-(2-fluoro-4-nitrophenyl-1,2,4-triazine-3,4(2H,4H)-dione. The latter is then reacted first with sodium hydride in dimethylformamide followed by methyl iodide to yield 2-(2-fluoro-4-nitrophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter is treated with iron powder in acetic acid to yield 2-(4-amino-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter dione is treated first with sodium nitrite in acetone and hydrochloric acid, then with methyl acrylate, and lastly with copper (I) chloride to form methyl 2-chloro-3-[5-fluoro-4-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-1-yl]phenyl]propionate. The latter is then nitrated by treatment with a mixture of nitric acid and sulfuric acid to form methyl 2-chloro-3-[5-fluoro-4-[4-methyl-1,2,4-triazine-3,5(2H,4H)-dione-1-yl]-2-nitrophenyl]propionate. The latter is dissolved in acetic acid and added to a hot suspension of iron powder in acetic acid, then heated at an elevated temperature (e.g. 80°-90° C.) for about one hour to form 1-(3-chloro-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-methyl-1,2,4-triazine-3,5,(2H,4H)-dione. The latter is dehydrohalogenated with triethylamine in tetrahydroduran to yield 1-[6-fluoroquinolin-2(1H)-one-7-yl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione. The latter is dissolved in dimethylformamide and treated first with potassium carbonate followed by propargyl chloride to yield 1-[6-fluoro-1-[2-propynyl]quinolin-2(1H)-one-7-yl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:16]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[O:26])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(O)c1ccccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
From 2.3 g of 3,5-bistrifluoromethyl aniline and 1.5 g of phthalic anhydride used as starting materials, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(Cl)Cl.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>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Oc1ccc(Br)cn1
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: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1ncc2cc(-c3ccc(=O)[nH]c3)ccc21
Temperature: 80 °C

Procedure:
The suspension of 5-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and 2N sodium carbonate solution (1.0 mL, 2 mmol) in DMF (2.1 mL) was degassed with N2 for 5 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.04 mmol), and the resulting mixture was heated at 80° C. overnight. The mixture was then diluted with CH2Cl2, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].[CH2:34](O)[CH:35]([CH3:37])[CH3:36].Cl.O1CCOCC1>>[CH2:34]([O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10])[CH:35]([CH3:37])[CH3:36]
Reactant: CC(C)CO
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCC(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 111.8 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (15.0 mg, 32 μmol) was combined with isobutyl alcohol (876 μL, 9.5 mmol). A solution of 4 M HCl in dioxane (282 μL, 1.1 mmol) was added, and the resulting mixture was stirred for 15 minutes at room temperature. The mixture was concentrated by rotary evaporation and the product lyophilized to yield the title compound (19 mg, purity 99%) as a white powder TFA salt. MS m/z [M+H]+ calc'd for C26H28ClFN4O5, 531.17. found 531.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][S:30][CH2:31][CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][S:30][CH2:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CSCCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSCCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 69.3 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (3-methylsulfanyl-propyl)-amide (69 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (82 mg), 3-methylthio-propylamine (38 mg), HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 497.
Reaction SMILES: C([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.[ClH:28]>C(O)C.[Pd]>[ClH:28].[F:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:11]([CH2:10][NH:9][CH3:8])[CH2:20][CH2:19]2
Reactant: Fc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC[C@H]1CCc2cc(F)ccc2[C@H]1c1ccccc1

Procedure:
To a mixture of 2-(N-benzylmethylamino)methyl-6-fluoro-1-phenyl-3,4-dihydronaphthalene (0.95 g) in ethyl alcohol (50 cm3) and hydrochloric acid (5 M, 1 cm3) was added palladium on charcoal (5%, 0.25 g). The resultant mixture was stirred under an atmosphere of hydrogen at a pressure of 2 atm at room temperature for 60 h. The catalyst was removed by filtration through a pad of Dicalite® and the solvent was evaporated under reduced pressure to provide the title compound (0.75 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[C:23](I)=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[CH:36])=[CH:31][N:30]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]2[C:23]([C:36]#[C:35][C:32]3[CH:31]=[N:30][C:29]([NH2:28])=[CH:34][CH:33]=3)=[C:22]([CH3:25])[N:21]=[C:20]([NH2:26])[N:19]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(-c2cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 733 mg (1.5 mmol) [3-(2-amino-5-iodo-6-methyl-pyrimidin-4-yl)-5-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (A-41) and 262 mg (2.2 mmol) 2-amino-5-ethynyl-pyridine (A-15) using 28 mg (0.15 mmol) CuI, 104 mg (0.15 mmol) PdCl2(PPh3)2 and 2 mL (15 mmol) triethylamine in 14 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel (DCM/MeOH gradient). Yield: 632 mg (88%).
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[CH:18]([CH3:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(O)C>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:18]([C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:27])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C(=O)c1ccccc1)N1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 146.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)piperazine dihydrochloride (5 g, 20 mmol), anhydrous KHCO3 (70 mmol) and 2-bromo-1-phenylpropan-1-one (3.96 ml, 26 mmol) in 40 ml of anhydrous ethanol was refluxed for 8 hours, and then treated according to general preparation 2 to give 6.1 g of compound (IV-2), yield 59.51%, mp 260-262° C. M+ 342.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.[C:10]1([S:16]([C:19]2[CH:20]=[C:21]([CH:39]=[CH2:40])[C:22]3[O:31][C:30]4[CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][C:25]=4[C:23]=3[CH:24]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl.O>[C:10]1([S:16]([C:19]2[CH:20]=[C:21]([CH2:39][CH2:40][B:4]3[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:9])([CH3:1])[O:3]3)[C:22]3[O:31][C:30]4[CH2:29][CH2:28][N:27]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:26][C:25]=4[C:23]=3[CH:24]=2)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: C=Cc1cc(S(=O)(=O)c2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(CCB4OC(C)(C)C(C)(C)O4)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a suspension of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.05 mL, 0.33 mmol) and Rh(CO)(PPh3)2Cl (2 mg, 2.7 mmol) in dichloromethane (4 mL) at ambient temperature was added tert-butyl 8-(phenylsulfonyl)-6-vinyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (120 mg, 0.27 mmol). The reaction mixture was stirred for 4 h then diluted with water and extracted with dichloromethane. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 8-(phenylsulfonyl)-6-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (85 mg, 55%) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 8.01-7.92 (m, 3H), 7.72 (br s, 1H), 7.58-7.46 (m, 3H), 4.56 (s, 2H), 3.97 (q, J=6.4 Hz, 2H), 3.83 (br s, 2H), 3.16 (t, J=6.4 Hz, 2H), 2.86 (br s, 2H), 1.51 (s, 9H), 1.39-1.19 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:11]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(Br)cc(C(=O)OC)c2N)cc1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of methyl 3-amino-2,6-dibromoisonicotinate (5.00 g, 16.1 mmol), 4-methoxycarbonylphenylboronic acid (2.90 gm, 16.1 mmol), and tetrakis-(triphenylphosphine)palladium(0) (0.932 g, 0.807 mmol) in a flask was flushed with nitrogen. Toluene (70 mL), MeOH (14 mL), and a 2 N aqueous solution of sodium carbonate (18 mL, 37 mmol) were added and the reaction was heated in a 120° C. oil bath for 4 hr. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, and brine. It was dried with sodium sulfate and the solvents removed. Flash silica gel chromatography (elution with hexane containing 10% EtOAc) afforded methyl 3-amino-6-bromo-2-(4-(methoxycarbonyl)phenyl)isonicotinate (2.0 gm). MS (ESI) m/z 365.0 and 367.0 (M+H). 1H NMR (CDCl3) δ ppm 8.15 (2H, d, J=8.24 Hz), 7.84 (1H, s), 7.71 (2H, d, J=8.24 Hz), 5.94 (2H, br. s.), 3.94 (6H, d, J=5.19 Hz).
Reaction SMILES: Br[CH2:2][C:3]([F:15])=[CH:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[CH:4]=[C:3]([F:15])[CH2:2][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C=C(F)Cc1ccc(F)c(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-bromo-4-(p-chlorophenyl)-2-fluoro-4-methyl-2-pentene, (Z)—(320.8 mg, 1.1 mmol), bis(dibenzylideneacetone)palladium(O) (Pd(dba)2, 31.6 mg, 0.055 mmol) in toluene (8 mL) is treated with potassium carbonate (608 mg, 4.4 mmol), degassed, treated with a solution of 4-fluoro-3-phenoxybenzeneboronic acid (331.8 mg, 1.43 mmol) in ethanol (2 mL), refluxed for 45 minutes, cooled to room temperature, and filtered through diatomaceous earth. The filtrate is diluted with ethyl acetate, and the resultant solution is washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless liquid (401 mg, 91% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])=[N:15][CH:14]=[N:13][C:12]=3[S:16][C:17]=2[CH2:22]1)=[O:30]
Reactant: C[C@@H](Nc1ncnc2sc3c(c12)CCNC3)c1ccccc1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: C[C@@H](Nc1ncnc2sc3c(c12)CCN(C(=O)/C=C/CN(C)C)C3)c1ccccc1

Procedure:
In analogy to Example 89, the title compound was prepared from N-[(1R)-1-phenylethyl]-5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 18A (100 mg, 0.32 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (75 mg, 0.45 mmol) to yield 23 mg (17%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].C(O/[C:25](/[CH3:32])=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>C(O)C>[NH2:12][C:11]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:2]=2[N:1]=[C:25]([CH3:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)/C=C(/C)OCC
Reactant: COc1ccc(Cn2c(N)c(C#N)c3c2CCCC3)cc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(c1N)c1c(n2Cc2ccc(OC)cc2)CCCC1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield from 2-amino-3-cyano-1-(4-methoxyphenyl)methyl-4,5,6,7-tetrahydroindole (D5) and ethyl β-ethoxycrotonate in a procedure similar to Description 6. Product was obtained as beige crystals from ethanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][C:12]2([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:13]2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].Cl>C(Cl)Cl>[CH3:41][S:42]([O:31][CH2:30][C:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27][C:12]2([O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:13]2)[CH2:11]1)(=[O:44])=[O:43]
Reactant: COc1ccc(CN2CC3(CCCC(CO)(COCc4ccccc4)C3)OC2=O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CC3(CCCC(COCc4ccccc4)(COS(C)(=O)=O)C3)OC2=O)cc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of 7-((benzyloxy)methyl)-7-(hydroxymethyl)-3-(4-methoxybenzyl)-1-oxa-3-azaspiro[4.5]decan-2-one (5.26 g, 12.36 mmol) in DCM (56 mL) at RT was added DIEA (4.32 mL, 24.7 mmol) and methanesulfonyl chloride (1.25 mL, 16.1 mmol). After 1 h, 2N HCl (100 mL) was added to the reaction. The layers were separated, and the aqueous layer was washed with DCM (100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified on a 80 g silica gel column (10-70% EtOAc/hexanes, 30 min gradient; 70% EtOAc/hexanes, 5 min; 60 mL/min elution; 254 nm detection) to afford (3-{[4-(Methyloxy)phenyl]methyl}-2-oxo-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl methanesulfonate (5.71 g, 87% yield). MS (m/z) 504.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 83 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved in 80 ml of tetrahydrofuran (abbreviation: THF), and the temperature was lowered to −78° C. 7.5 ml (12.0 mmol) of n-BuLi (1.6M) was dropped into the reaction solution by a dropping funnel, and it was stirred for 1 hour. A solution in which 5 g (20.0 mmol) of iodine was dissolved in 20 ml of THF was dropped and stirred for 2 hours at −78° C. After reaction, a sodium thiosulfate water solution was added to stop the reaction. An organic layer was washed with a sodium thiosulfate water solution and a saturated saline and dried with magnesium sulfate. After the natural filtration, the filtrate was concentrated and the obtained solid was recrystallized by ethanol. Then, 3.1 g of a light-yellow solid of 9-iodo-10-phenylanthracene, which was the intended object, was obtained with a yield of 83% (synthetic scheme of (b-5)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:5][CH:4]=1.[I:15]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:15][C:14]1[CH:13]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: II
Reactant: COc1ccc(Cc2nc[nH]n2)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc(Cc2nc[nH]n2)cc1I
Reaction time: 72 h

Procedure:
To a solution of 3-(4-methoxybenzyl)-1H-1,2,4-triazole (335 mg, 1.770 mmol) in MeOH (5 ml) under nitrogen at RT was added silver sulfate (552 mg, 1.770 mmol) followed by iodine (449 mg, 1.770 mmol). Added a second equivalent of silver sulfate and stirred for 3 days. The reaction did not go to completion. The solids were filtered washing with MeOH, the filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel, eluting with MeOH in DCM to afford the title compound contaminated with ca. 20% of starting material. Mass spectrum (ESI) 316.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].O>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:28][C:29](=[O:31])[CH3:30])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)=O
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (5.0 g, 16 mmoles) and potassium carbonate (10.62 g, 77 mmoles) in DMF (25 ml) was added chloroacetone (2.32 g of 90% , 22 mmoles) and the mixture stirred vigorously for 5 hours, followed by pouring into water (130 ml) and filtration to give, after drying, 4.57 g of crude product. This was dissolved in methylene chloride and filtered over a short alumina column, followed by concentration and recrystallization of the residue from toluene to give 4.16 g (78%) of the title compound as white solid, mp 105°-106.5°. The NMR (90 MHz) in CDCl3 gave the following resonances: δ 8.44 (s, 1H); 6.16 (s, 1H); 4.72 (s, 2H); 4.4 (s, 2H); 3.6 (m, 2H); 2.68 (m, 6H); 2.28 (s, 3H); 1.08 (t, 6H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:20]=[O:21])C>>[C:1]([O:21][CH:20]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12][C:11]1=[O:16])([CH3:7])([CH3:6])[CH3:2]
Reactant: CN(C)C=O
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: CC(C)(C)OC=C1C(=O)Nc2ccc(-c3ccccc3)cc21
Yield: 10 %

Procedure:
A solution of 0.62 g (3.0 mmol) of 5-phenyl-1,3-dihydro-indol-2-one (Hewawasam and Meanwell, Tetrahedron Letters 1994, 35, 7303-6) in 10 mL of DMF was treated with 0.90 g (4.5 mmol) of DMF di-tert-butyl acetal for 2 h at rt. DMF was removed under high vaccum, and the residue was subjected to chromatography on silica gel, eluting with hexane:EtOAc (1:1), to yield 0.09 g (10%) of 3-tert-butoxymethylene-5-phenyl-1,3-dihydro-indol-2-one: 1H NMR (DMSO-d6): δ1.46 (s, 9H), 6.85 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.3 Hz, 1H), 7.34-7.39 (m, 1H), 7.41 (d, J=7.5 Hz, 2H), 7.53 (d, J=7.5 Hz, 2H), 7.72 (s, 1H), 7.83 (s, 1H), 10.28 (s, 1H); APCI+MS m/z 316 (M+23)+. Further elution with EtOAc:MeOH (98:2) gave 0.11 g (14%) of 3-dimethylaminomethylene-5-phenyl-1,3-dihydro-indol-2-one.