Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2[N:19]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][O:13]3)[N:20]=[CH:21][CH:22]=2)=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccnn2C2CCCCO2)ccc1[N+](=O)[O-]

Procedure:
5-Chloro-2-nitrobenzonitrile (1.5 g), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.74 g), PEPPSI ((1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (3-chloropyridyl)palladium(ii) dichloride) (0.11 g), K2CO3 (2.27 g) in DMF (30 ml) and water (3 ml) was stirred under argon at 90° C. for 2.5 h. After pouring the mixture to water, it was extracted with EtOAc. Combined organic phases were washed with 5% NaHCO3, water and brine, dried with Na2SO4 and evaporated. The residue was triturated with ethanol. The precipitate was filtered and washed with water. Yield 1.96 g. 1H-NMR (400 MHz; d6-DMSO): δ 1.50-1.65 (m, 3H), 1.83-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.42 (m, 1H), 3.60-3.67 (m, 1H), 3.95-4.00 (m, 1H), 5.34 (d, 1H), 6.82 (d, 1H), 7.68 (d, 1H), 8.11 (dd, 1H), 8.32 (d, 1H), 8.54 (d, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.I[C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([CH3:13])[CH:12]=1>CCCCCC.C(OCC)(=O)C>[CH3:14][C:9]1[CH:8]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:12]=[C:11]([CH3:13])[CH:10]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: c1cc[nH]c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-n2cccc2)c1
Yield: 99 %

Procedure:
Using general procedure B, pyrrole (83 μL, 1.2 mmol) was coupled with 5-iodo-m-xylene to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 9:1) provided 0.170 g (99% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.07 (t, J=7.0 Hz, 2H), 7.02 (s, 2H), 6.89 (s, 1H), 6.33 (t, J=7.0 Hz, 2H), 2.37 (s, 6H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>O1CCCC1.[Pt]=O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCOc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Agent: O=[Pt]
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ccc(CCC(=O)OC)cc2)cc1
Yield: 99.4 %

Procedure:
A mixture of Methyl 3-[4-(4-pentyloxyphenyl)phenyl]acrylate (2.70 g) and platinum oxide (0.41 g) in tetrahydrofuran (40 ml) was stirred for 8 hours under 3 atom of hydrogen at ambient temperature. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give Methyl 3-[4-(4-pentyloxyphenyl)phenyl]propionate (2.70 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11]([CH3:21])([CH3:20])[O:10][C:9]2=[O:22])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.F[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=1[N+:41]([O-:43])=[O:42]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:12]2[C:11]([CH3:20])([CH3:21])[O:10][C:9](=[O:22])[N:8]2[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][C:34]=3[N+:41]([O-:43])=[O:42])[CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1(C)OC(=O)N(C2CCC(N)CC2)[C@H]1c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccc(C#N)cc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Yield: 94 %

Procedure:
To a vial charged with (S)-3-(4-aminocyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.353 g, 1.152 mmol) were added ACN (3.84 mL), DIEA (0.402 mL, 2.304 mmol) and 4-fluoro-3-nitrobenzonitrile (commercially available from J & W Pharmlab, Levittown, Pa.) (0.191 g, 1.152 mmol) respectively. After completion of reaction, the dark mixture was dried under reduced pressure and purified with a 25 g HP spherical silica column ramping DCM:MeOH (90:10) in DCM from 0-50%, then isocratic at 50% (detection at 215 nm) leading to isolation of product which was obtained as an orange/brown oil as a mixture of cis/trans isomers of (S)-4-((4-(4-(4-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)cyclohexyl)amino)-3-nitrobenzonitrile (0.490 g, 1.083 mmol, 94% yield). m/z (ESI) 453.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:17][CH2:18][CH3:19])[C:12]=2[C:11](=[O:20])[NH:10][C:9]1=[O:21].Cl[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:37])([CH3:36])[C:28]#[C:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].O>CN(C)C=O>[CH2:34]([N:31]([CH2:32][CH3:33])[CH2:30][C:29]#[C:28][C:27]([OH:37])([CH3:36])[CH2:26][CH2:25][CH2:24][CH2:23][N:10]1[C:11](=[O:20])[C:12]2[N:13]([CH2:17][CH2:18][CH3:19])[CH:14]=[N:15][C:16]=2[N:8]([CH3:7])[C:9]1=[O:21])[CH3:35]
Reactant: CCN(CC)CC#CC(C)(O)CCCCCl
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN(CC)CC)c(=O)n2C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2.12 g (15.3 mmol) of potassium carbonate were added to a solution of 2.0 g (9.6 mmol) of 3-methyl-7-propylxanthine in 60 ml of dimethylformamide at 60° C. and the mixture was stirred at 60° C. for one hour. Then 3.07 g (12.5 mmol) of 1-chloro-8-diethylamino-5-hydroxy-5-methyl-6-octyne from stage A1) were added dropwise and the mixture was stirred at 80° C. for 12.5 hours. It was then allowed to cool to room temperature, water was added, and three extractions with tert-butyl methyl ether were carried out. The organic phase was dried over magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography, dichloromethane/methanol=19/1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]2[C:15]([CH3:16])=[CH:14][NH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][N:13]3[C:7]4[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:5]([O:4][CH3:3])[C:6]=4[C:15]([CH3:16])=[CH:14]3)=[CH:26][CH:25]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: COc1nc(SC)nc2[nH]cc(C)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 54.2 %

Procedure:
In an argon gas stream, 60% sodium hydride-oil (220 mg) was suspended in anhydrous DMF (5 ml) and a powder of 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (1.05 g) was added in small portions with ice-cooling and stirring. After completion of addition, the mixture was stirred for 30 minutes and then a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in DMF (5 ml) was added. Then, at room temperature, the mixture was stirred for 2 hours. To this reaction mixture was added water (50 ml) and the resulting precipitate was collected by filtration, rinsed with water, dried, and purified by flash column chromatography (silica gel; hexane: ethyl acetate=9:1) to provide the title compound (1.19 g). 1H-NMR (CDCl3) δ: 2.33(3H,d,J=1.2Hz), 2.60(3H,s), 4.08(3H,s), 5.36(2H,s), 6.57(1H,d,J=1.2Hz), 7.28(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.70(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz).
Reaction SMILES: COC1C=C(N2CCC(C3C=CC=CC=3N)C2)C=CC=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:67][CH2:66][N:65]([C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=4)[CH2:64]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][N:56]([CH2:55][CH3:54])[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:67][CH2:66][N:65]([C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=4)[CH2:64]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cccc(N2CCC(c3ccccc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1cccc(N2CCC(c3ccccc3N)C2)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCN(c2cccc(OC)c2)C1

Procedure:
Synthesized from 2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl]{2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (180 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl{2-[1-(3-methoxyphenyl) pyrrolidin-3-yl]phenyl}amine (153 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (140 mg).
Reaction SMILES: [Cl:1][C@H:2]1[CH2:20][C@@:17]2([CH2:18][CH3:19])[C@@H:13]([C@@H:14]([OH:22])[CH2:15][C:16]2=[O:21])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[C:24]([O:22][C@@H:14]1[C@H:13]2[C@H:12]3[C@H:3]([C@H:2]([Cl:1])[CH2:20][C@:17]2([CH2:18][CH3:19])[C:16](=[O:21])[CH2:15]1)[C@@H:4]1[C:9](=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1)[CH2:10][CH2:11]3)(=[O:26])[CH3:25]
Reactant: CC[C@]12C[C@H](Cl)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC[C@]12C[C@@H](Cl)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.6 g of 11β-chloro-15α-hydroxy-18-methyl-4-estrene-3,17-dione in 5 ml of pyridine is stirred at room temperature under argon with 1.2 ml of acetic anhydride. After 18 hours, the solution is introduced into hydrochloric-acid-containing ice/water. The thus-precipitated product is vacuum-filtered, dissolved in ethyl acetate, and washed with water. Recrystallization of the crude product from isopropyl ether yields 1.0 g of 15α-acetoxy-11α-chloro-18-methyl-4-estrene-3,17-dione, mp 125.0° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])#[N:2].N.[H][H]>C(O)(C)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8]
Reactant: CCP(=O)(CCC#N)OC(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CC(C)O
Product: CCP(=O)(CCCN)OC(C)C

Procedure:
To 34.1 g of isopropyl 2-cyanoethyl(ethyl)phosphinate in 500 ml of isopropanol are added 60 ml of liquid ammonia and 6.8 g of Raney-Nickel. The mixture is heated to 80° and treated with hydrogen at 100 bar. After 11/2 hours hydrogen-uptake stops. The reaction mixture is filtered and the filtrate distilled to give isopropyl 3-aminopropyl(ethyl)phosphinate as a colorless oil, b.p. 75°/13 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)=[O:24])([O-:19])=[O:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of 3,5-dichloroaniline (8.1 g) and triethylamine (7.0 ml) in chloroform (100 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (9.3 g) in chloroform (50 ml). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate. The resultant precipitate was collected and washed with chloroform and water to give 3-nitro-N-(3,5-dichlorophenyl)benzamide (12.50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: COc1n[nH]c(=O)[nH]1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1n[nH]c(=O)n1Cc1cccc(Br)c1
Reaction time: 6 h
Yield: 29.9 %

Procedure:
To a solution of 2.30 g (20 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 20 ml acetonitrile was added 2.90 g (21 mmol) of potassium carbonate. A solution of 5.00 g (20 mmol) of 3-bromobenzylbromide in 20 ml of dry acetonitrile was added dropwise thereto at 55° C. After the mixture was stirred at the same temperature for additional 6 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (5.2 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane and the solid was washed, ice-cooled, collected by filtration and concentrated. Further, to the resultant solid residue was added tert-butyl methyl ether and the solid was washed, cooled, collected by filtration and dried to obtain 1.70 g (5.98 mmol) of 4-(3-bromobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Fc1ccccc1Br
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
After dissolving 1.64 ml of 1-bromo-2-fluorobenzene in 30 ml of tetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise while stirring, and after 1 hour, a solution of 2.50 g of 1-benzyl-4-piperidineacetaldehyde [CAS No.120014-32-6] in tetrahydrofuran (10 ml) was added and stirring was continued for 1 hour. After adding water to the reaction solution, the temperature was raised to room temperature and extraction was performed with ethyl acetate. The organic layer was washed With water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.15 g, 60% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:9][CH:10]([OH:31])/[CH:11]=[CH:12]/[C:13]1[N:14]([CH3:30])[C:15](=[O:29])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[OH:1][CH:2]([CH2:9][CH:10]([OH:31])/[CH:11]=[CH:12]/[C:13]1[N:14]([CH3:30])[C:15](=[O:29])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(O)CC(O)/C=C/c1c(-c2ccccc2)c2ccccc2c(=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(/C=C/C(O)CC(O)CC(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A solution of ethyl (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-hept-6-enoate (0.35 g; prepared as described in Example 1) in methanol (15 ml) was cooled to 10° C. and treated with a solution of sodium hydroxide (0.17 g) in water (10 ml) dropwise during 10 minutes. The reaction mixture was warmed to room temperature, stirred for one hour and evaporated to dryness, and the residual solid, which was crude sodium (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoate, was dissolved in water (50 ml). The aqueous solution was washed with diethyl ether (20 ml) and acidified to pH 5 by treatment with glacial acetic acid. The resulting yellow solid was filtered off and washed well with water, to give (E)-3,5-dihydroxy-7-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)hept-6-enoic acid (0.10 g), m.p. 170° C. [Elemental analysis: C, 70.0; H, 5.92; N, 3.37%; calculated: C, 70.2; H, 5.89; N, 3.56%].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:11]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:11]([C:17]2[N:18]=[N:19][N:20]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 24 h
Yield: 63.7 %

Procedure:
To a suspension of 0.64 g (16 mmol) 50% sodium hydride in 7.5 mL of dry dimethylformamide was added 5.7 g (16 mmol) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate and the resultant mixture stirred for 30 minutes. To the resultant solution, 5.7 g (18 mmol) bromotriphenylmethane was added and the mixture stirred for 24 hours. The mixture was diluted to 200 mL with water and the insolubles collected by filtration. The product was recrystallized from ethyl acetate to give 6.1 g of the title compound; m.p.=161°-162° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([SH:18])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([S:18][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:14][CH2:13]2)=[O:11])=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(S)CC1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)CSC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.08 h

Procedure:
A mixture of 1-p-nitrobenzyloxycarbonyl-4-mercaptopiperidine (1.19 g), t-butyl bromoacetate (780 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (608 mg) in benzene (10 ml) was stirred for 5 minutes under nitrogen atmosphere. The reaction mixture was washed successively with water, dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to give 1-p-nitrobenzyloxycarbonyl-4-t-butoxycarbonylmethylthiopiperidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]=[CH2:11])[C:5]([NH2:12])=[CH:4][CH:3]=1.CN([CH:16]=[O:17])C.O=C1CCC(=O)C1OC(=O)OC1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH:10]=[CH2:11])[C:16](=[O:17])[NH:12][C:5]2=[CH:4][CH:3]=1
Reactant: C=CCNc1nc(Cl)ccc1N
Reactant: CN(C)C=O
Agent: O=C(OC1C(=O)CCC1=O)OC1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=CCn1c(=O)[nH]c2ccc(Cl)nc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
6-Chloro-N-(prop-2-en-1-yl)pyridine-2,3-diamine (71-3, 9.52 g, 51.8 mmol, 1.0 equiv) was added to anhydrous DMF (55 mL) to give a dark purple solution. Bis(2,5-dioxocyclopentyl)carbonate (13.18 g, 51.8 mmol, 1.0 equiv) was added in one portion to give a dark green solution. The resulting reaction mixture was then heated to 80° C. After 18 h, the reaction contents were cooled to RT, diluted with EtOAc (100 mL) and added slowly to saturated aqueous NaHCO3 (200 mL). The layers were separated and the aqueous layer was back-extracted with 3×100 mL EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give a dark purple residue. Purification by normal-phase HPLC provided 5-chloro-3-(prop-2-en-1-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (71-4) as a tan solid. LRMS (M+H)+: observed=210.0, calculated=209.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][N:40]([C:13]([C:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:9][O:10][C:11]=3[CH3:16])=[O:15])[CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (587 mg, 1.35 mmol, 74%) was obtained.
Reaction SMILES: CC1(C)[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:35][CH2:36][CH2:37][CH2:38][C@H:4]2[O:3]1.C(N(CC)CC)C>C(Cl)Cl.Cl>[O:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][O:26][C:24]2[CH:23]=[CH:22][C:21]3[N:17]([CH2:16][C:14]4[CH:13]=[CH:12][C:10]5[N:11]=[C:7]([NH:6][C@@H:5]6[CH2:35][CH2:36][CH2:37][CH2:38][C@H:4]6[OH:3])[S:8][C:9]=5[CH:15]=4)[CH:18]=[N:19][C:20]=3[CH:25]=2)[CH2:34][CH2:33]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCN5CCOCC5)ccc43)cc2s1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(OCCN5CCOCC5)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
To a stirred mixture of (3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholino ethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (85 mg, 0.15 mmol) from the previous step in DCM (10 mL) at 0° C. was added methanolic HCl (3 drops). The reaction mixture was stirred at 0° C. for 10 min. The mixture was adjusted to pH˜7 by addition of triethylamine and then concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 25%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.97 (m, 1H), 7.62 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.17 (d, J=6.9 Hz, 2H), 6.83 (m, 1H), 5.41 (s, 2H), 4.73 (d, J=5.4 Hz, 1H), 4.08 (t, J=11.7 Hz, 2H), 3.57 (t, J=9.1 Hz, 4H), 3.47-3.52 (m, 2H), 2.68 (t, J=11.7 Hz, 2H), 2.46 (t, J=9.3 Hz, 4H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59-1.63 (br s, 2H), 1.16-1.28 (m, 4H). LCMS (ESI) m/z 508 (M+H)+.