Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:13]>>[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13]
Reactant: NCCc1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCCc2ccccc2)CC1

Procedure:
The product was prepared from benzeneethanamine and 1,4-trans cyclohexanedicarboxylic acid monomethyl ester by the method described in Example 6 (a) mp 120°-124°.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8](Cl)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H].O.O.O.C([O-])(=O)C.[Na+]>CO.[Pd]>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1ncc(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1

Procedure:
A solution of 21.8 g (47.5 mmol) of tert-butyl 2-[4-(2-butyl-4-chloro-5-formyl-imidazol-1-yl-methyl)phenyl]-2-cyclopentyl-acetate in 200 ml of methanol is hydrogenated at a hydrogen pressure of about 2 bar for 1 h at 25° C. in the presence of 2.18 g of palladium on active carbon (5% strength) and 6.47 g (47.5 mmol) of sodium acetate trihydrate. The solution is then filtered off from the catalyst and concentrated, and the residue is chromatographed on silica gel 60 using ethyl acetate/petroleum ether (1:1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=1>O1CCOCC1.ClCCl>[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([O:12][CH2:11][CH2:10][C:7]2[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[NH:9][CH:8]=2)[N:15]=1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: Clc1cncc(Cl)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
K-t-BuO (2.32 g, 20.6 mmol) was added to a stirred solution of tryptophol (1.7 g, 10.6 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After being stirred for 10 min at 0° C. and 10 min at room temperature, the mixture was chilled to 0° C. (ice-bath) and 2,6-dichloropyrazine (1.37 g, 9.17 mmol) was added. The yellowish reaction mixture was stirred at 0° C. for 30 min and for a further 20 min at room temperature. The mixture was diluted with dichloromethane, filtered, and concentrated in vacuo to furnish a brownish oil. This material was purified by chromatography on silica gel (14×5 cm) using n-hexane/ethyl acetate (75:25). This furnished 1.38 g (55%) of the title compound as a beige solid. Purity>90% by 1H NMR in CDCl3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([O:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCN
Reaction time: 7 h
Yield: 77 %

Procedure:
In this synthesis CDTAMA is reacted with the monoprotected diamine N-(t-butyoxycarbonyl)-1,6-diaminohexane to give the corresponding amide. The t-Boc protecting group is then hydrolyzed to give the product. To prepare the monoprotected diamine N-(t-butyoxycarbonyl)-1,6-diaminohexane, first 9.4 g (81.2 mmol) of 1,6-diaminohexane is dissolved in 60 ml dry chloroform and 0.85 ml (6.1 mmol) triethylamine is added. To this solution is added dropwise 1 g (4.1 mmol) [2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-ON) dissolved in 20 ml dry chloroform. This solution is stirred 7 hr, filtered and the filtrate evaporated to an oil. This oil is vacuum distilled to remove the excess 1,6-diaminohexane. The residue in the distillation flask is dissolved in acetone and purified on a silica gel chromatography column (eluted with acetone) to give 0.68 g (77%) of N-(t-butoxycarbonyl)-1,6-diaminohexane as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH:35]=C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:50]CC1>C(OCC)C.O.O=[Os](=O)(=O)=O>[CH2:1]([O:8][CH2:9][C@@:10]1([N:37]2[CH:45]=[C:43]([CH3:44])[C:41](=[O:42])[NH:40][C:38]2=[O:39])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:32])[CH3:31])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:12]([CH2:34][CH:35]=[O:50])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@H]1C[C@](COCc2ccccc2)(n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Os](=O)(=O)=O
Solvent: CCOCC
Solvent: O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CC=O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
A solution of 18 (1 mmol), OsO4 (0.1 mmol) and 4-methylmorpholine N-oxide (2 mmol) in diethyl ether and water are stirred overnight. A solution of NaIO4 is added and the solution further stirred. The aqueous layer is extracted with diethyl ether and the combined organic layer is evaporated under vacuum to yield the crude product, compound 55.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:15][CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[C:6]=2[CH:7]=1.O1CCCC1.C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCCC>[O:9]1[CH2:10][CH2:11][O:12][C:8]21[C:6]1[CH:7]=[C:2]([C:26]([OH:28])=[O:27])[CH:3]=[CH:4][C:5]=1[S:15][CH2:14][CH2:13]2
Reactant: Brc1ccc2c(c1)C1(CCS2)OCCO1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)C1(CCS2)OCCO1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
13.58 g (0.047 mol) of the title compound of Step C was added to 150 mL of tetrahydrofuran. The solution was cooled to about -65° C. and 23 mL (0.057 mol) of 2.5 M n-butyllithium in hexane (purchased from Aldrich Chemical Company) was added dropwise while keeping the temperature below -55° C. After stirring under nitrogen for 1 h, excess solid CO2 was added in one portion, and the mixture was stirred overnight while warming to room temperature. 100 mL of hexane was added to the mixture, and it was then filtered. To the solid residue was added 500 mL of water and 400 mL of methylene chloride. The solution was cooled to about 0° C., acidified to pH 1 with concentrated hydrochloric acid, and extracted with methylene chloride (3×400 mL). The resulting solution was dried (MgSO4), filtered, and evaporated to dryness to yield 8.58 g of the title compound of Step D as a solid melting at 186.7° C. (dec). 1H NMR (Me2SO-d6): δ2.2 (m,2H), 3.2 (m,2H), 4.1 (m,4H), 7.2-8.0 (3H), 12.8 (br s,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:11]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:32][O:33][C:34]1[CH:40]=[CH:39][C:37]([O-:38])=[CH:36][CH:35]=1.[Na+:41]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O-:9])=[CH:5][CH:4]=1.[Na+:41].[CH3:32][O:33][C:34]1[CH:40]=[CH:39][C:37]([O:38][C:11]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Reactant: COc1ccc(O)cc1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Oc2ccc(OC)cc2)cccc1Oc1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Sodium 4-methoxyphenoxide was prepared as described in part A using 4-methoxyphenol (156 mg, 1.25 mmol) and was dried in vacuo. A solution of ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate (304 mg, 1.0 mmol) in DMSO was added to the sodium 4-methoxyphenoxide at 25° C. and the mixture was stirred until all the solid had dissolved (approximately 20 min.). Stirring was continued at 25° C. for an additional 24 hr. The reaction mixture was then warmed to 60° C. and stirred for 2 hr., then stirred for 4 hr. at 80° C. At this time all of the ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate had been consumed, as judged by thin layer chromatography (TLC). The reaction was cooled to 25° C., diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic extract was washed with water (2×7 ml) and brine (7 ml), dried (MgSO4) and concentrated to give a light yellow oil. The crude product was purified by flash chromatography (SiO2, 50% CH2Cl2/hexane—CH2Cl2) giving 195 mg of ethyl 2-(4-methoxyphenoxy)-6-[3,4-(methylenedioxy)phenoxy]benzoate. (47% yield, m.p. 84.5-85° C.).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][NH:36][CH3:37])[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]([OH:54])=O)[CH2:47][CH2:46]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[F:43][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8](=[O:39])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:38])[C:29]2([CH2:35][N:36]([CH3:37])[C:52](=[O:54])[CH2:51][N:48]3[CH2:47][CH2:46][O:45][CH2:50][CH2:49]3)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]2)[CH:10]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: CNCC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CC1(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)C=CC=CN1)C(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
Into a 50-mL vial, was placed N-(3-(trifluoromethyl)benzyl)-2-(2-(2-((methylamino)methyl)picolinamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (10 mL), 2-morpholinoacetic acid (28.9 mg, 0.20 mmol, 1.20 equiv), EDC HCl (47.4 mg, 0.25 mmol, 1.50 equiv), and 4-dimethylaminopyridine (30.4 mg, 0.25 mmol, 1.50 equiv). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×50 mL of aqueous NH4Cl, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 116 mg (59%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 9.12 (m, 1H), 8.86 (d, J=9.2 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.17 (m, 1H), 8.12 (m, 1H), 8.01 (m, 1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.60 (m, 3H), 4.96 (m, 2H), 4.72 (s, 2H), 4.50 (m, 2H), 3.98 (m, 4H), 3.70 (m, 4H), 3.1 (s, 3H), 2.10 (m, 4H), 1.98 (s, 2H). MS (ES, m/z): 730 [M+H]+.
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:25]2[C:2]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:3])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:22][CH:21]=1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Yield: 42.7 %

Procedure:
Distilled THF (50 mL) was added to 3-chloro-3-(4-chlorophenyl)isobenzofuran-1(3H)-one (1.50 g, 5.76 mmol) followed by 4-chlorobenzylamine (0.77 mL, 6.34 mmol) and triethylamine (0.96 mL, 6.91 mmol) as for general procedure A and recrystallised in acetonitrile to give pure white solid 2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (945 mg, 2.46 mmol. 43%). Rf 0.54 (40:60 EtOAc:petrol). Mp. 156.5-157.4° C. λmax (CH3OH)/nm 221.0, Abs 0.850. IR: 3159, 1659, 1487, 1468 cm−1. 1H NMR (300 Hz, CDCl3); δ 3.07 (s, br, 1H, OH), 4.01 (d, 1H, J=15.0 Hz, N—CH2), 4.52 (d, 1H, J=15.0 Hz, N—CH2), 7.05 (m, 4H, Ar—H), 7.16-7.21 (m, 5H, Ar—H), 7.42 (m, 2H, Ar—H), 7.73 (m, 1H, Ar—H). 13C NMR (75 Hz, DMSO); δ 42.6 (N—CH2), 91.5 (Ar2(O)CN), 123.1, 124.0, 128.2, 128.7, 129.1, 130.4, 130.6, 133.4, 133.5, 135.0, 136.8, 137.0, 148.8 (Ar), 168.0 (C═O). LC/MS-ES+ m/z 406.1, 366.0, 244.9, 242.9, 161.0. Anal. Calcd. for C21H15Cl2NO2.0.2H2O: C, 65.03; H, 4.00; N, 3.61%. Found C, 65.08; H, 4.06; N, 3.88%. HRMS (EI) m/z: 244.0291. Found 244.0299.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([O:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[CH2:27][C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]#[C:45][C:46]([OH:49])([CH3:48])[CH3:47])(=[O:37])=[O:36])=[O:33])=[CH:30][C:29]=2[O:52][CH3:53])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH:8]1([O:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[CH2:27][C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]#[C:45][C:46]([O:49][C:1](=[O:3])[CH3:2])([CH3:48])[CH3:47])(=[O:36])=[O:37])=[O:33])=[CH:30][C:29]=2[O:52][CH3:53])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CC(C)(C)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CC(C)(C)OC(C)=O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.44 g of acetic anhydride and 0.1 g of 4-dimethylaminopyridine are added to a solution of 1.0 g of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxybenzoyl]-2-(3-hydroxy-3-methyl-but-1-yn-1-yl)-benzenesulfonamide in 6 ml of pyridine. The reaction solution is stirred for 20 hours at room temperature under argon. The reaction mixture is subsequently diluted with 100 ml of ethyl acetate. The ethyl acetate phase is washed twice with 80 ml of 1N hydrochloric acid each time, with 50 ml of water and with 50 ml of saturated sodium chloride solution. The ethyl acetate phase is dried over magnesium sulfate and concentrated by evaporation at 20 torr and 40°. The residue is chromatographed on 50 g of silica gel (Merck, ST 60, 40-63 μm) with hexane/ethyl acetate=1/1 to yield the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.87 (b, 1H); 8.06 (d, d, 1H); 7.61 (m, 3H); 7.55 (d, 1H); 7.50 (d, 1H); 7.41 (d, d, 1H); 7.22 (d, 1H); 7.14 (d, d, 1H); 7.13 (d, 1H); 6.94 (s, 1H); 5.06 (m, 1H); 3.95 (s, 2H); 3.90 (s, 3H); 3.66 (s, 3H); 1.91 (s, 3H); 1.89-1.52 (m, 8H); 1.61 (s, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:33]4[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[CH:35][CH:34]=4)[N:15]3[CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].[F-].[Cs+].[OH:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1.O>COCCOC.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>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]([C:5]3[S:6][C:2]([C:62]4[CH:61]=[CH:60][CH:59]=[C:58]([OH:57])[CH:63]=4)=[C:3]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:4]=3)=[O:8])[CH:17]=2)[CH:13]=[C:14]1[C:33]1[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Reactant: OB(O)c1cccc(O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Yield: 81.6 %

Procedure:
A mixture of 5 (60 mg, 0.075 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), CsF (34 mg, 0.22 mmol), 3-hydroxyphenylboronic acid (16 mg, 0.12 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 min and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 6 as a yellow amorphous solid (50 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 2H), 8.04 (s, 1H), 7.74-7.61 (m, 7H), 7.56 (d, J=8.0 Hz, 2H), 7.49-7.26 (m, 6H), 7.13 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 5.40 (s, 2H), 4.32 (t, J=7.2 Hz, 2H), 4.16-4.06 (m, 2H), 3.72 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 1.72-1.69 (m, 2H), 1.49-1.46 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.62, 171.45, 168.65, 166.21, 157.16, 149.47, 143.69, 141.59, 138.00, 137.26, 137.23, 136.09, 134.28, 131.99, 131.82, 130.66, 130.37, 130.33, 130.12, 129.33, 128.90, 128.62, 128.53, 123.49, 121.88, 121.13, 120.87, 116.54, 116.46, 112.82, 104.20, 67.20, 61.46, 43.92, 37.36, 34.81, 27.45, 25.84, and 14.42.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC([N:7]2[C:20]3[C:15](=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=3)=CC=1.[C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH:39]=[CH:38][C:37]([N:40](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[CH:43][CH:42]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:17]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:19][C:20]([N:40]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[CH:52]=[CH:51][C:50]4[N:7]([C:8]5[CH:9]=[CH:10][C:11]([C:8]6[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=6)=[CH:12][CH:13]=5)[C:20]5[C:15](=[CH:16][C:17]([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=6)=[CH:18][CH:19]=5)[CH2:14][C:49]=4[CH:48]=3)=[CH:43][CH:42]=2)[C:37]2[CH:36]=[CH:35][C:34]([C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)=[CH:39][CH:38]=2)=[CH:15][CH:16]=1
Reactant: CC1(C)OB(c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Reactant: Brc1ccc2c(c1)Cc1cc(-c3ccccc3)ccc1N2c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N(c3ccc(-c4ccccc4)cc3)c3ccc(-c4ccc5c(c4)Cc4cc(-c6ccccc6)ccc4N5c4ccc(-c5ccccc5)cc4)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
10-(biphenyl-4-yl)-2-bromo-7-phenyl-9,10-dihydroacridine (14 g, 28.6 mmol) was dissolved in toluene (500 mL) under a nitrogen atmosphere. Then, N-(biphenyl-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)biphenyl-4-amine (15 g, 28.6 mmol) was added thereto. To the resultant mixture solution, tetrakis triphenyl phosphine palladium (1.32 g, 1.14 mmol) and potassium carbonate (9.9 g, 71.5 mmol) were added. Then, distilled water (70 mL) was added thereto, followed by reflux-stirring for 4 hours. The resultant solution was cooled to about 60° C., and purified by silica gel. Then, a toluene layer was extracted. The extracted organic solvent was concentrated and removed, and methanol was added to produce a solid. Through filtration, a yellowish brown solid was obtained. It was purified through silica gel column chromatography (methylene chloride/n-hexane (1/10)) to obtain N-(biphenyl-4-yl)-N-(4-(10-(biphenyl-4-yl)-7-phenyl-9,10-dihydroacridin-2-yl)phenyl)biphenyl-4-amine as a Cpd 14 compound (15 g, yield 65%, pale yellow solid).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.[F:27][C:28]([F:36])([F:35])[C:29]1([C:32](O)=[O:33])[CH2:31][CH2:30]1>>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:22])([CH3:23])[C@:12]([C:15]2[CH:16]=[C:17]([NH:21][C:32]([C:29]3([C:28]([F:36])([F:35])[F:27])[CH2:31][CH2:30]3)=[O:33])[CH:18]=[CH:19][CH:20]=2)([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(N)c2)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cccc(NC(=O)C3(C(F)(F)F)CC3)c2)N=C1N

Procedure:
The coupling of [(R)-4-(3-amino-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F1) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=397.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[C:13]([Cl:17])[C:14]([Cl:16])=[CH:15][C:8]=2[N:7]=1)([OH:5])[CH3:4].[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].C[O-].[Na+]>CO>[Cl:16][C:14]1[C:13]([Cl:17])=[CH:12][C:9]2[N:10]([CH3:11])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:28][C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:27][CH:26]=3)=[N:7][C:8]=2[CH:15]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: Cn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(SCC(C)(O)c2nc3cc(Cl)c(Cl)cc3n2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-methyl-1H-benzoimidazol-2-yl)-propan-2-ol (60 mg) in MeOH (2 mL) at room temperature was added a solution of 4-acetamidothiophenol (40 mg) and sodium methoxide (0.047 mls of 25 wt % in MeOH). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The crude product was purified by flash chromatography (25%-100% EtOAc/hexanes) to yield the title compound as a white foam solid.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+].C(O)C>O>[CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[N:15]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=[N:17][N:18]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12

Procedure:
A mixture of 30 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole, 16.6 parts of benzyl bromide, 3.53 parts of sodium hydroxide, 120 parts of ethanol and 60 parts of water was refluxed for 64 hours. The mixture was cooled, was extracted with chloroform and the chloroform extract washed with sodium bicarbonate solution and water. Evaporation of the chloroform gave a residue which was chromatographed in silica gel. Elution with 3 : 1 toluene/acetic acid and chloroform gave, after crystallisation from ethanol, a total of 7.31 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole, m.p. 92.5°-94°C.