Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][NH:14][C:7]2=[N:6][C:5]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)([O-:3])=[O:2].[CH2:21]([CH:25]1[CH2:27][O:26]1)[CH:22]([CH3:24])[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CN(C=O)C>[OH:26][CH:25]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:27][N:14]1[C:7]2=[N:6][C:5]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)=[C:4]([N+:1]([O-:3])=[O:2])[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13]1
Reactant: O=c1c([N+](=O)[O-])c(-c2ccncc2)nc2n1CCCN2
Reactant: CC(C)CC1CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)CC(O)CN1CCCn2c1nc(-c1ccncc1)c([N+](=O)[O-])c2=O
Temperature: 80 °C

Procedure:
In a 100 mL RBF with stirrer bar was charged 3-nitro-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (1.0 g) and 2-isobutyl-oxirane (0.7 g) in DMF (7 mL) under nitrogen. A solution of LiHMDS (1N in THF, 7 mL) was added to the mixture, resulting a red solution. Affter being heated at 80° C. overnight the mixture was cooled to room temperature and was partitioned between CH2Cl2 and NH4Cl (aq.). The organic phase was further washed with H2O, dried with Na2SO4, concentrated, and eluted on silica gel (0–7% 2N NH3-MeOH in DCM) to afford the product that was used directly in the next step. M+1 374.
Reaction SMILES: Cl[C:2]1[C:3]([C:20]#[N:21])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](B2OC(C)(C)C(C)(C)O2)=[C:27]([NH:29]C(=O)OC(C)(C)C)[CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]2=[C:2]3[C:3](=[C:20]([NH2:21])[N:29]=[C:27]2[CH:28]=1)[N:4]=[CH:5][C:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)=[CH:7]3
Reactant: CCCOc1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
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: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-(4-propoxyphenethyl)picolinonitrile (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.1 eq.), tetrakis(triphenylphosphine)palladium (8 mol %), and 2N aqueous sodium carbonate solution (3.0 eq.) in toluene (0.2 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM. The two phases were separated. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give 8-methyl-2-(4-propoxyphenethyl)benzo[f][1,7]naphthyridin-5-amine. 1H NMR (Acetone-d6): δ 8.74 (s, 1H), 8.67 (s, 1H), 8.24 (d, 1H), 7.41 (s, 1H), 7.15-7.17 (m, 3H), 6.81 (d, 2H), 6.5 (br, 2H), 3.87 (t, 2H), 3.18 (t, 2H), 3.04 (t, 2H), 2.44 (s, 3H), 1.73 (m, 2H), 0.99 (t, 3H). LRMS [M+H]=372.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Yield: 97 %

Procedure:
1-bromo-4-iodobenzene was reacted with trimethylsilylacetylene via Sonogashira coupling reaction under the PdCl2(PPh3)2/CuI/TEA catalyst system to produce (4-bromophenylethynyl)trimethylsilane as a white solid, quantitatively. Specifically, 11.32 g (40 mmol) of 1-bromo-4-iodobenzene was placed in a round bottomed flask equipped with a septum and a stirring bar. The flask was put into a glove box and 281 mg (0.4 mmol) of dichlorobis-(triphenylphosphine)palladium(II) and 19 mg (0.1 mmol) of CuI were added. Afterward, 100 mL of dried triethylamine and 5.65 mL (40 mmol) of trimethylsilylacetylene were injected into the flask through syringes while stirring. The mixture was stirred at room temperature for 2 h. Precipitates were formed. The precipitates were filtered and washed with diethyl ether. The solutions were combined and the solvent was evaporated. The crude product was purified by a silica gel column chromatography using hexane as eluent. A white powdery product was obtained in 97% yield (9.82 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-:9].[K+].Br[CH2:12][CH2:13][CH2:14][C:15]1[C:35]2[NH:36][C:17](=[CH:18][C:19]3[C:20]([CH2:48][CH3:49])=[C:21]([CH3:47])[C:22]([N:46]=3)=[CH:23][C:24]3[NH:28][C:27]([CH:29]=[C:30]4[N:37]=[C:33]([CH:34]=2)[C:32]([CH2:38][CH2:39][CH2:40]Br)=[C:31]4[CH3:42])=[C:26]([CH3:43])[C:25]=3[CH2:44][CH3:45])[C:16]=1[CH3:50]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH2:14][C:15]2[C:35]3[NH:36][C:17](=[CH:18][C:19]4[C:20]([CH2:48][CH3:49])=[C:21]([CH3:47])[C:22]([N:46]=4)=[CH:23][C:24]4[NH:28][C:27]([CH:29]=[C:30]5[N:37]=[C:33]([CH:34]=3)[C:32]([CH2:38][CH2:39][CH2:40][O:9][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[C:31]5[CH3:42])=[C:26]([CH3:43])[C:25]=4[CH2:44][CH3:45])[C:16]=2[CH3:50])=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5CCCBr)C(CCCBr)=C4C)c(C)c3CC
Reactant: [OH-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5CCCOc1ccc(N)cc1)C(CCCOc1ccc(N)cc1)=C4C)c(C)c3CC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
3.28 g (30.10 mmol) of 4-aminophenol and 1.69 g (30.10 mmol) of powdered potassium hydroxide are stirred in 50 ml of anhydrous dimethylformamide under argon for 30 minutes at room temperature and then mixed with 2.00 g (3.01 mmol) of 13,17-bis-(3-bromopropyl)-3,8-diethyl-2,7,12,18-tetramethylporphyrin (CA RN 112635-99-1). After 30 hours of stirring at room temperature, it is filtered, substantially concentrated by evaporation in a vacuum, the residue is taken up in methylene chloride and shaken out once each with water and with saturated aqueous sodium bicarbonate solution. The organic phase is dried on sodium sulfate, filtered and concentrated by evaporation and the residue is chromatographed to aluminum oxide with methylene chloride/methanol. After the concentration by evaporation, the product is obtained as reddish brown solid, which can be recrystallized from methylene chloride/ether.
Reaction SMILES: [CH3:1][C:2]1([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=4)[CH2:23][CH2:22]3)[C@@H:17]([CH3:34])[CH2:16]2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.Cl>O1CCOCC1>[CH3:34][C@H:17]1[CH2:16][N:15]([C:2]2([CH3:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)[CH2:20][CH2:19][N:18]1[CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]([F:33])([F:31])[F:32])[CH:28]=2)[CH2:23][CH2:22]1
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(C2(C)CCNCC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 152.9 %

Procedure:
tert-Butyl 4-methyl-4-{(3S)-3-methyl-4-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidine-1-carboxylate (0.32 g, 0.6 mmol) was dissolved in a 4 M; solution of HCl in dioxane (8.0 mL). After being stirred at room temperature for 2 hrs, the solution was concentrated to give the title compound (0.35 g) as a trihydrochloride salt. MS calculated for C21H30F3N3: (M+H)+ 382; found 382.2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:34])(=[O:33])[NH2:32])=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:33])(=[O:34])[NH:32][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:21][CH:20]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
By the procedure of Example 13, Step C, 5-n-butyl-2-(2-chlorophenyl)-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Example 13, Step B) was reacted with 4-fluorobenzoyl chloride. Column chromatography on silica gel (gradient elution with 0.5-5% MeOH in CH2Cl2) afforded an 80% yield of the title compound as cream-colored crystals, mp 118°-120° C., satisfactory purity by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 619 (M+1)+
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][CH2:28][N:29]=[N+:30]=[N-:31])=[O:16])[CH:12]=[CH2:13].O>CN(C)C=O.C(OCC)(=O)C>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][CH2:28][N:29]=[N+:30]=[N-:31])[CH2:19]1)(=[O:10])[CH3:8]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCN=[N+]=[N-]
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a suspension of potassium t-butoxide (6.99 g) in dimethylformamide (150 ml) was added thioacetic acid (4.45 ml) under ice-cooling. After stirring for 15 minutes, a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-methanesulfonyloxypyrrolidine (15.3 g) in dimethylformamide (20 ml) was added to the mixture under ice-cooling. The mixture was warmed to 80° C. and stirred for 4 hours, then cooled to ambient temperature and poured into water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with sat. sodium bicarbonate, water (twice) and brine, dried over magnesium sulfate, and evaporated under reduced pressure to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-azidoethyl) pyrrolidine (14.7 g).
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([CH3:12])[C:4]=1[Br:13])C.CO.Cl>O1CCCC1>[Br:13][C:4]1[C:5]([CH3:12])=[C:6]([CH2:7][OH:8])[CH:10]=[CH:11][CH:3]=1
Reactant: CCc1ccc(C(=O)O)c(C)c1Br
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1CO
Yield: 90 %

Procedure:
Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ7.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([C:12]([O:14]CC)=O)=[CH:8][C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:6]2)[CH2:3][CH2:2]1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>C1(C)C(C)=CC=CC=1>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([C:12](=[O:14])[NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:8][C:7]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: NCc1ccccn1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CC2)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(C(=O)NCc3ccccn3)c(=O)n(CC3CC3)n2)cc1
Yield: 84.2 %

Procedure:
In xylene, 2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2-(aminomethyl)pyridine were reacted at 140° C. for 1 hour. Post-treatments were conducted as in Example 58-(3), whereby the title compound was obtained in a yield of 84.2%.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:18]([NH:29][CH3:30])[C@@H:17]([CH3:31])[CH2:16]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43].Cl.O1CCOCC1.C(=O)(ON1C(=O)CCC1=O)OC(C)(C)C>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@@H:15]1[CH2:16][C@H:17]([CH3:31])[C@H:18]([N:29]([CH3:30])[C:42](=[O:43])[O:44][CH3:45])[C@H:19]([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:28])[CH2:20]1
Reactant: CN[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: CC(C)(C)OC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)[C@H]1[C@@H](C)C[C@@H](c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-3-methyl-2-(methylamino)cyclohexyl)carbamate (1.0 equiv.) in DCM (0.05 M) at 0° C. was added DIEA (3.0 equiv.) and then methyl chloroformate (1.5 equiv.). The homogeneous solution was left standing at 0° C. at for 4 hrs. The reaction was quenched partitioned between NaHCO3 solution and EtOAc. The organic layer was washed with Brine, dried over Na2SO4, concentrated and purified by ISCO chromatography. The product was treated with 4 M HCl in dioxane (30.0 equiv.) at rt for 1 hour. The volatiles were removed in vacuo and the solid was pumped on for 5 minutes on the high vac. To the residue was added CH2Cl2 (0.15 M), DIEA (5.0 equiv.) and tert-butyl 2,5-dioxopyrrolidin-1-yl carbonate (1.6 equiv.). The solution was left stirring at rt for 1 hr. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-methyl ((1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl)(methyl)carbamate in 20% yield. LC/MS (m/z)=393.2 (MH+), Rt=0.60 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:16][CH:17]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([F:26])[C:20]=1[Cl:27])[CH3:18].[CH3:28][P:29](Cl)([CH3:31])=[O:30].C(N(CC)CC)C>ClCCl>[Cl:27][C:20]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[CH:17]([O:16][C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][P:29]([CH3:31])([CH3:28])=[O:30])=[CH:12][CH:13]=2)[CH:4]=1)[CH3:18]
Reactant: CP(C)(=O)Cl
Reactant: CC(Oc1cc(-c2ccc(CO)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-c2ccc(COP(C)(C)=O)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.2 %

Procedure:
a mixture of [4-[6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-3-pyridyl]phenyl]methanol (15 mg, 0.037 mmol), dimethylphosphoryl chloride (50 mg, 0.45 mmol), and triethylamine (0.5 mL) in dichloromethane (10 mL) was stirred at room temperature for 1.5 hours. The solvent was removed and the residue was purified by HPLC (water/methanol, 10˜100%) to give the title compound (2 mg, 11%). ESMS: m/z 483 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:19])([CH3:18])[C:7](=[O:17])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:46][OH:47].CN([CH:51]=[O:52])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:46]([O:52][CH3:51])=[O:47])[CH:10]=2)[C:6]([CH3:19])([CH3:18])[C:7]1=[O:17]
Reactant: COCCCCN1C(=O)C(C)(C)c2ccc(Br)cc21
Reactant: CN(C)C=O
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)OC)cc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 6-bromo-1-(4-methoxybutyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.0 g) were added palladium acetate (207 mg), triphenylphosphine (484 mg), triethylamine (0.86 ml), methanol (0.62 ml), and DMF (10 ml), and the mixture was stirred at 100° C. under carbon monoxide atmosphere for 4 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the title compound (480 mg) as a pale yellow liquid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O1CCN(C2C=CC(C=O)=CC=2)C[CH2:26]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].N[C:49]1[CH:50]=[C:51]([CH:55]=[CH:56][C:57]=1[NH2:58])[C:52]([OH:54])=[O:53]>O.CC(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([C:22]([NH:58][C:57]5[CH:56]=[CH:55][C:51]([C:52]([O:54][CH3:26])=[O:53])=[CH:50][CH:49]=5)=[O:24])=[CH:21][C:15]=4[N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccc3[nH]c(-c4ccc(N5CCOCC5)cc4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Compound 167 was prepared according to the general procedure similar to that described in Scheme III. Preparation of 2-(4-morpholinophenyl)-1H-benzo[d]imidazole-5-carboxylic acid: 4-Morpholinobenzaldehyde (475 mg, 2.5 mmole), sodium metabisulfite (85 mg) and 3,4-diaminobenzoic acid (152 mg, 2.7 mmole) were placed in a 10-mL microwave tube and 5.0 mL HPLC grade 2-propanol added. The reaction mixture was microwaved at 170° C. for 55 minutes. The reaction mixture was added dropwise to 25 mL water and stirred at room temperature for 30 min. then it was filtered and washed with plenty of water, ethyl acetate and hexanes and dried to provide the pure intermediate acid (323 mg, 40% yield). This compound was used for next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=O)[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:20]=[CH:19][C:11]3[NH:12][C:13](=[S:30])[O:14][C:15]([CH3:17])([CH3:16])[C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 52.7 %

Procedure:
A mixture of 6-(3-chlorophenyl)-4,4-dimethyl-1,4-dihydro-benzo[d]-[1,3]oxazin-2-one (0.15 g, 0.5 mmol) and Lawesson's reagent (0.24 g, 0.6 mmol) in anhydrous o-xylene was heated at reflux under nitrogen for 3 hours. The solvent was removed and the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/6:1) to afford the title compound as a white solid (80 mg, 52%): mp 183-184° C.; 1H-NMR (DMSO-d6) δ 12.25 (s, 1H, D2O exchangeable), 7.78 (t, 1H, J=1.7 Hz), 7.63-7.70 (m, 3H), 7.49 (t, 1H, J=7.8 Hz), 7.42 (d, 1H, J=8.1 Hz), 7.12 (d, J=8.8 Hz), 1.72 (s, 6H); MS (EI) m/z 303 (M+, 100%), 305 (M+, 32%); Anal. Calcd. For C16H14ClNOS: C, 63.26; H, 4.64; N, 4.61. Found: C, 63.37; H, 4.62; N, 4.54.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)=[N+:22]=[N-:23]
Reactant: O=C(c1ccc(I)cc1)c1ccc(OCCCBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of (4-(3-bromopropoxy)phenyl)(4-Iodophenyl)methanone (50.0 g, 112 mmol), and sodium azide (10.2 g, 157 mmol) was dissolved in DMF (300 ml). The reaction was heated to 45° C. and left to stir overnight. Upon completion, the reaction mixture was filtered to remove sodium salt and concentrated under reduced pressure. The crude was then further extracted with chloroform, the organic layer was washed with brine, and dried over anhydrous sodium sulfate to afford 40.3 g (88.0% yield) of (4-(3-azidopropoxy)phenyl)(4-iodophenyl)methanone as grey solid.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 21 h
Yield: 94.8 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 4-fluorophenol (5.00 g, 44.6 mmol) and 4-fluorobenzaldehyde (4.00 mg, 32.2 mmol) was added potassium carbonate (13.4 g, 96.6 mmol), which was stirred for 21 hours at 80° C. The reaction solution was then cooled to room temperature, water was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane=1:15→1:10) to obtain the title compound (6.60 g, 90.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: Cc1c(-c2ccc(F)cc2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-fluoro-phenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [H-].[Na+].[O:3]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4]1.[CH3:18][CH2:19][OH:20]>>[CH2:19]([O:20][CH2:4][C:5]1([OH:3])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h

Procedure:
To anhydrous EtOH (20 mL) was added slowly NaH (124 mg, 52 mmol) at 0° C., and after the addition was complete the mixture was stirred for 1.5 h. Then tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9B, 45 mmol) was added, and the resulting mixture was stirred at 50° C. for 1 h, when TLC showed that s.m. was consumed. Then the mixture was neutralized with 1N aq. HCl, and concentrated. The residue was purified by prep-TLC to give the desired product 9C as colorless oil (600 mg)1H NMR (METHANOL-d4) δ: 3.78 (d, J=12.6 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H), 3.22-3.29 (m, 2H), 3.15 (br. s., 2H), 1.48-1.60 (m, 4H), 1.43 (s, 9H), 1.18 (t, J=7.0 Hz, 3H).