Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(SC2Cc3ccccc3C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(SC2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(p-methoxyphenylthio) indane (5 g) in dry dichloromethane (40 ml) was cooled to -70°. Boron tribromide (6 g) was added slowly with stirring at -70°. When addition was complete, the reaction mixture was kept at -70° for a further 10 minutes and then allowed to warm to room temperature. The mixture was left overnight and water (70 ml) then added slowly with stirring. The mixture was then poured into water (65 ml) and a further quantity (95 ml) of dichloromethane added, and the mixture agitated. The dichloromethane solution was separated and extracted with 2 molar sodium hydroxide. The cloudy extract was allowed to stand until it cleared and was then decanted from a residue. The solution was acidified with dilute hydrochloric acid and extracted with ether. The ether solution was washed with water, dried, and evaporated to give 2-(p-hydroxyphenylthio)indane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: CCCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C
Yield: 54 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:39]2[CH:51]=[CH:50][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:40]=[CH:41][C:42]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:50][CH:51]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][S:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCSCC1
Temperature: 100 °C
Yield: 73 %

Procedure:
A solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzamide (800 mg, 1.629 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (740 mg, 2.443 mmol), sodium carbonate (621 mg, 5.86 mmol) in 20 ml of dioxane was degassed with argon for 20 min, Pd(PPh3) (188 mg, 0.16 mmol) was added to the mixture and heated to 100° C. overnight. The reaction was cooled to room temperature and diluted with water, compound was extracted in 10% MeOH in DCM, dried over Na2SO4, concentrated and crude was purified by silica gel (100-200) chromatography to obtain the title compound (700 mg, 73.0%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(F)ccc21
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 50 (286 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 333 mg (87%) of white solids. M.P. 263° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.62 (m, 4H), 3.95 (m, 4H), 6.66 (d, J=3.6 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.65 (m, 3H), 7.88 (s, 1H). EIMS m/z 403 (M+23). Anal. (C20H17FN4O3) C, H, N.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C:9](=S)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C:17]=3[CH:30]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:33][NH2:34].C(O)(=O)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C(O)C>[C:1]1([CH2:7][NH:8][C:9]2[NH:34][N:33]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][C:17]=4[CH:30]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(C(=O)CC(=S)NCc3ccccc3)cc2C1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cc(NCc4ccccc4)[nH]n3)cc2C1
Temperature: 78 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
A mixture of 1,1-dimethylethyl 7-{3-[(phenylmethyl)amino]-3-thioxopropanoyl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (155 mg, 0.35 mmol), hydrazine monohydrate (66 mg, 0.59 mmol), acetic acid and Lawesson's reagent (63 mg, 1.0 mmol) in ethanol (5 mL) was stirred at 78° C. for one hour. The reaction mixture was cooled, concentrated and the residue purified directly by silica gel chromatography (5% methanol in dichlomethane) to give 1,1-dimethylethyl 7-{5-[(phenylmethyl)amino]-1H-pyrazol-3-yl}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (92 mg, 62% yield). MS (EI) for C24H28N4O3: 421 (MH+).
Reaction SMILES: [C:1]1([S:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:30]1([I+]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>O.C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[C:1]1([S+:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Sc3cccc4ccccc34)cccc2c1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: O=C([O-])c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: c1ccc([S+](c2cccc3ccccc23)c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Di(1-naphthyl)sulfide (3 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copper benzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ether was added and the mixture vigorously stirred overnight to achive solidification. Filtration and washing with ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 4.8 g (90%) of the title compound, di-(1-naphthyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)OCc1cccs1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) and 385 mg (2.00 mmol) methanesulfonic acid thiophen-2-ylmethyl ester in 20 mL DMF is added 451 mg (3.26 mmol) potassium carbonate at RT. The reaction mixture is stirred overnight at RT and is diluted with 60 mL of EtOAc. The organic phase is washed three times with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[O:6][C:5]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[CH2:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:4][C:3]1=[O:26].ClC1C(=O)CC(C2CCCC2)(CCC#CC2C=CC=C(O)C=2)OC1=O.[CH3:52][C:53]1[CH:58]=[C:57]([CH3:59])[N:56]2[N:60]=[C:61]([SH:63])[N:62]=[C:55]2[N:54]=1>>[CH:9]1([C:5]2([CH2:14][CH2:15][NH:16][C:17](=[O:25])[CH2:18][CH2:19][C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[CH2:4][C:3]([OH:26])=[C:2]([S:63][C:61]3[N:62]=[C:55]4[N:54]=[C:53]([CH3:52])[CH:58]=[C:57]([CH3:59])[N:56]4[N:60]=3)[C:7](=[O:8])[O:6]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: O=C(CCc1ccco1)NCCC1(C2CCCC2)CC(=O)C(Cl)C(=O)O1
Agent: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Product: Cc1cc(C)n2nc(SC3=C(O)CC(CCNC(=O)CCc4ccco4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The desired product was prepared analogously to example F(7), substituting N-[2-(5-chloro-2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-3-furan-2-yl-propionamide from Step 3 below in place of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione and 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol in place of 2-mercaptothiazole. Yield: 11 mg, 8%. MS (ESI): 524 (M−H).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([CH3:36])[N:35]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:36][C:34]1[N:35]=[C:30]([CH3:29])[C:31]2[N:32]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:37]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1cnc(N)c(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)n1
Temperature: 130 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (770 mg, 1.61 mmol, 1.0 eq), 3,5-dimethylpyrazin-2-amine (CAS-Nr. 91678-81-8, 218 mg, 1.77 mmol, 1.1 eq) and diisopropylethylamine (0.28 mL, 1.61 mmol, 1.0 eq) in 10 mL isopropanol was added 3 Å molsieves. The reaction mixture was heated to reflux temperature for 2 h. No conversion was observed under these conditions (UPLC-MS). Therefore, the reaction mixture was heated to 130° C. for 1 h under microwave conditions (single mode microwave oven). The reaction mixture was filtered to remove the molsieve and the filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera, 25 g Snap cartridge, DCM→DCM/ethanol 95/5) to deliver 249 mg (31%) of the title compound.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:11]=1[C:12]#N.C([O:22]CC)C>>[NH2:9][C:10]1[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[CH:14][C:11]=1[C:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: N#Cc1cc(Cl)c(F)cc1N
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Product: Nc1cc(F)c(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of phenylmagnesium bromide (7.18 ml, 3M solution in diethyl ether, 21.5 mmol) in diethyl ether (15 ml) was added to a solution of 2-amino-5-chloro-4-fluoro-benzonitrile (1225 mg, 7.18 mmol) in diethyl ether (20 ml) at 0° C. The reaction mixture was then stirred at reflux for 2 h, cooled to room temperature and quenched carefully by addition of 2N HCl (˜40 ml). The mixture was heated to 55° C. for 3 h and then cooled to room temperature again. 3N NaOH (˜20 ml) was added carefully at 0° C. to adjust the pH to 9. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 95:5-90:10) to afford the title compound (1667 mg, 93%) as yellow solid. MS (ESI): 250.3 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[C:33]([O:36][CH:37]([O:39][C:40](OC1C=CC([N+]([O-])=O)=CC=1)=[O:41])[CH3:38])(=[O:35])[CH3:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:33]([O:36][CH:37]([O:39][C:40]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH2:20][O:21][C:22]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=4[CH:24]=3)(=[O:18])=[O:17])[CH2:12][C:11]2=[O:30])=[CH:31][CH:32]=1)=[NH:3])=[O:41])[CH3:38])(=[O:35])[CH3:34]
Reactant: N=C(N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)NC(=N)c1ccc(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)cc1
Yield: 41.7 %

Procedure:
A solution of 1-(4-amidinobenzyl)-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone hydrochloride (99 mg), O-(1-acetoxyethoxycarbonyl)-4-nitrophenol (54 mg), diisopropylethylamine (39 mg) in DMF (5 ml) was stirred at 80° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated. Precipitated crystals were washed with ether to give colorless crystals of the title compound (49 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cccnc3F)ccc1-2
Yield: 20 %

Procedure:
Following the procedure for 128, 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 2-fluoropyridin-3-ylboronic acid were reacted to give 487 (0.226 g, 20%). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=8.3, 1H), 8.33-8.18 (m, 2H), 8.12 (s, 1H), 7.54-7.45 (m, 2H), 7.37 (d, J=1.5, 1H), 5.96-5.75 (m, 1H), 4.44 (t, J=5.0, 2H), 3.49 (t, J=5.0, 2H), 1.90-1.28 (m, 6H). MS (ESI(+)): m/z 408.12 (M+H)
Reaction SMILES: [N+](C1C=CC(C=O)=CC=1)([O-])=O.[CH2:12]([O:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)C=Cc1ccc(N)cc1

Procedure:
The above approach could be used to convert 4-nitrobenzaldehyde (Aldrich) into 3-(4-nitrophenyl)propenoic acid ethyl ester. The latter compound could be reduced (J. Am. Chem. Soc., 1944, 66, 1442) to give 3-(4-aminophenyl)propenoic acid ethyl ester. Reaction of (4-aminophenyl)-propenoic acid ethyl ester with an omega-haloalkyl-isocyanate provides an 4-(omega-haloalkylaminocarbonyl)aminophenyl)propenoic acid ethyl ester (see., Khim. Farm. Zh. 1984, 18(12), 1432-1436). The latter compound can be reacted with sodium hydride to give a 4-(1,3-diaza-2-oxoalicyclylphenyl)propenoic acid ethyl ester (see., Bioorg. Med. Chem. Lett. 1999, 9(5), 749-754), the latter compound could be converted to give a 3-(4-(1,3-diaza-2-oxoalicycl-1-yl)phenyl)propenoic acid ethyl ester by the methods described in Bioorg. Med. Chem. Lett. 1999, 9(5), 749-754. The latter compound could be elaborated by methods described previously, to give a 3-(4-(1,3-diaza-2-oxoalicycl-1-yl)phenyl)-3-amino propanoic acid ethyl ester suitable for subsequent coupling.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1.[CH3:32][O:33][CH2:34][C:35]#[CH:36].C(NC(C)C)(C)C>[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:36]#[C:35][CH2:34][O:33][CH3:32])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1
Reactant: CC(C)Oc1cc(OCCCCl)cc2ncnc(Nc3c(Cl)cc(I)c4c3OCO4)c12
Reactant: C#CCOC
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Temperature: -10 °C

Procedure:
A mixture N-(5-chloro-7-iodo-1,3-benzodioxol-4yl)-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (1.313 g, 1:1 wt.:wt. mixture with triphenylphosphine), 3-methoxy-prop-1-yne (0.19 ml), palladium(II) bis-triphenylphosphine dichloride (0.080 g) and copper (I) iodide (0.022 g) was taken up into ethyl acetate (15 ml) and cooled to −10° C. This was set to stir rapidly and then diisopropylamine (0.32 ml) was added and the reaction was stirred cold for 45 minutes before being warmed to room temperature and left to stir for a further 90 minutes. The reaction mixture was then filtered through Celite under suction (washing the Celite with a further portion of ethyl acetate) then the combined filtrate solutions were evaporated under reduced pressure to leave a brown gum. The gum was then purified by column chromatography on silica using diethyl ether as eluent. There was thus obtained the title compound (as a 1:1.3 wt.:wt. mixture with triphenylphosphine) (1.056 g) as a yellow solid; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.30 (quin, 2H), 3.45 (s, 3H), 3.76 (t, 2H), 4.25 (t, 2H), 4.35 (s, 2H), 4.83 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.42 (s, 1H)—triphenylphosphine 7.46 (m, 6H), 7.54 (m, 3H), 7.67 (m, 6H);
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5][C@:4]([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([O:13][CH3:14])[CH2:3]1.[C:30](=O)([O:41]CCCC=C)[O:31][C:32]1C=[CH:36][C:35]([N+]([O-])=O)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:14][O:13][C@:4]1([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:3][C@H:2]([NH:1][C:30](=[O:41])[O:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5]1
Reactant: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Reactant: C=CCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCOC(=O)N[C@@H]1C[C@@H](CCCC=C)O[C@@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)C1
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of the title compound from Example 67 (113 mg, 0.269 mmol) in dichloromethane (2 mL) was treated with a solution of 4-nitrophenyl pent-4-enyl carbonate (88 mg, 0.35 mmol) in dichloromethane (0.8 mL), diisopropylethylamine (0.061 mL, 0.35 mmol), and a catalytic amount of DMAP (0.2 mg). The mixture was stirred for 24 h, after which it was chromatographed directly on silica gel, eluting with ethyl acetate/dichloromethane, to give the title compound (119 mg, 83%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.[C:12](Cl)(=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CC(N(C)C)=O.C(#N)C>[SH:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Nc1ccc2nc(S)[nH]c2c1
Reactant: CCCCCCCC(=O)Cl
Solvent: O
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: CCCCCCCC(=O)Nc1ccc2nc(S)[nH]c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
8.3 g of 5-amino-2-mercaptobenzimidazole was suspended in a mixture of 20 ml of dimethylacetamide and 35 ml of acetonitrile. 8.5 g of octanoyl chloride was dropped into the suspension at 50° C. After stirring at 50° C. for 2 hours, 20 ml of water was added to the reaction mixture. Crystals thus formed were collected by filtration, washed with water and dried to obtain 12.8 g of 2-mercapto-5-octanamidobenzimidazole (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.C(N=C=N[CH2:33][CH2:34][CH2:35][N:36](C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:36][CH:35]3[CH2:34][CH2:33][CH:5]([C:4]4[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=4)[CH2:6][CH2:7]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(c5ccccc5)CC4)cc3)c(Cl)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.0899 g, 0.238 mmol), N,N-dimethylpyridin-4-amine (0.00291 g, 0.0238 mmol), and (1R,4R)-4-phenylcyclohexanamine (0.0627 g, 0.358 mmol) in DMF (1.25 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.0549 g, 0.286 mmol), and the reaction was stirred overnight. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system eluting with a linear gradient of 5% to 50% EtOAc in hexanes to yield two isomers of the product. The first eluting isomer was collected and called isomer 1 (27 mg). The second eluting isomer was called isomer 2 (32 mg). The relative configurations of each of these isomers were not determined.