Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([N+:23]([O-])=O)[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:6][CH2:5]1)[CH3:3].O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([N:14]2[C:22]3[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([NH2:23])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:6][CH2:5]1)[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN1CCN(C(C)C)CC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: COc1cc2c(cc1N)N(C(=O)CCN1CCN(C(C)C)CC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 1-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.62 g, 1.65 mmol) in absolute ethanol (150 mL) and DMA (10 mL) was added tin (II) chloride dihydrate (2.23 g, 7.84 mmol) and 1M HCl(3.0 mL). After overnight stirring, reaction was quenched with excess saturated NaHCO3 solution, stirred for one hr, and filtered through a celite pad which was rinsed with methanol. After organic solvent removal, the aqueous layer was extracted with dichloromethane (2×200 mL), the organic layers were combined, adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 1-{3-[4-(1-methylethyl)-1-piperazinyl]propanoyl}-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=347.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].F[C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[C:17]1[C:16]([OH:23])=[CH:15][C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:13][C:12]=1N2.CS(C)=[O:32]>CCOC(C)=O.[NH4+].[Cl-]>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[C:17]1[C:16]([OH:23])=[CH:15][C:14]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:13][C:12]=1[O:32]2
Reactant: O=c1c2ccc(F)cc2[nH]c2cc(N3CCOCC3)cc(O)c12
Reactant: CN(C)CCO
Reactant: CS(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc2c(=O)c3c(O)cc(N4CCOCC4)cc3oc2c1

Procedure:
A suspension of KH (about 3 mg, 30-35% by weight in mineral oil) was added to a solution of N,N-dimethylethanolamine (14 mg, 0.16 mmol) and 6-fluoro-1-hydroxy-3-morpholin-4-yl-10H-acridin-9-one (25 mg, 0.08 mmol) in DMSO (1.0 mL), and the reaction mixture was heated at reflux for 4 hours. After cooling, the mixture was diluted with EtOAc and sat. NH4Cl. The organic layer was washed six times with water. The organics were dried (Na2SO4), then concentrated. The concentrate was purified via flash chromatography to yield 4 mg (13%). 1H NMR (CDCl3, 400 MHz) δ: 12.94 (s, 1H), 8.11 (d, 1H), 6.93 (d, 1H), 6.81 (s, 1H), 6.25 (d, 1H), 4.17 (t, 3H), 3.86-3.84 (m, 4H), 3.37-3.35 (m, 4H), 2.80 (t, 2H), 2.39 (s, 6H). LRMS (APCI, positive): Da/e 384.5 (m+1).
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2cc(C)ccn2)C[C@@H]1C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2cc(C)ccn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.1 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(4-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 71) (192.2 mg, 0.371 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (TFA) (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 1.5 h then concentrated in vacuo. The residue was loaded on a 5 g SCX cartridge then eluted with MeOH (20 mL) followed by 2M NH3 in MeOH (20 mL). The ammonia fractions were combined and concentrated in vacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient:1 to 10% (2M NH3 in MeOH) in DCM) gave a first residue which was purified by MDAP (modifier: formic acid) to give another residue which was dissolved in DCM (5 mL). The resulting solution was treated with HCl (1M in Et2O, 0.22 mL, 0.220 mmol) then concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(4-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (79.7 mg, 0.171 mmol, 46.1% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[CH3:12][O:13][CH2:14][CH2:15][Br:16]>>[BrH:16].[NH:1]=[C:2]1[N:6]([CH2:15][CH2:14][O:13][CH3:12])[CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3]1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: COCCBr
Product: Br
Product: CCOC(=O)c1cn(CCOC)c(=N)s1

Procedure:
A mixture of commercially available ethyl 2-aminothiazole-5-carboxylate (ABCR) and 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 231 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:6].[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O1CCCC1.O>C(OCC)(=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=3)=[CH:21][CH:20]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)CCCCl)c2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCl)Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1

Procedure:
4-{[2-(4-Chlorobutyrylamino)-4-pyridyl]oxy}aniline (100 mg), p-fluorophenyl isocyanate (0.037 ml) and tetrahydrofuran (3 ml) were stirred at room temperature for 25 minutes. Water and ethyl acetate were added to the reaction solution for extraction, NH type silica gel was added to the extract, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate and ethyl acetate:methanol=10:1). The solvent was distilled off under reduced pressure to obtain 56 mg of the target substance as a white solid.
Reaction SMILES: C(N(CC)C1C=CC([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=CC=1)C.CN(C)C1C=CC=C(N(C)C)C=1.C(OC(=O)C)(=O)C>CO>[Cl:19][C:18]1[C:17]([Cl:20])=[C:16]([Cl:21])[C:15]([Cl:22])=[C:11]2[C:10]=1[CH2:8][O:13][C:12]2=[O:14]
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Agent: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: O=C1OCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 90 °C
Yield: 103 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (3.61 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X = (CH3)2N, Y2 = H, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = Cl) (5.60 g., m.p. 206°-207.5° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8]C(OC(C)(C)C)=O)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][C:6]1[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: COC(=O)c1cc(Br)cc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)cc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.23 g of methyl 4-bromo-6-t-butoxycarbonylamino-pyridine-2-carboxylate was dissolved in 30 ml of chloroform, and then 15 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 1 hour. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=20/1) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=1.[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:20]1([C:26]2[N:27]=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[O:17])[CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)nc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)nc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [6-(trifluoromethyl)pyridin-3-yl]carbamate (200 mg, 0.593 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (145 mg, 0.593 mmol), diisopropylethylamine (0.207 ml, 1.19 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 48 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (110 mg, 42.8%) as a solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])O)=[CH:5][CH:4]=1.[NH3:12].CO.[Cl-].[NH4+].CCO>CO>[ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:12])=[NH:9])=[CH:5][CH:4]=1
Reactant: N
Reactant: Cc1ccc(C(=N)O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a solution of p-methylbenzimidate hydrochloride (8.00 g, 43.09 mmol) in MeOH (100 ml) is added NH3/MeOH solution (2.68M, 24.12 ml, 64.64 mmol). Upon the addition of the NH3, the mixture has a pH around 8.5. To this solution is added ammonium chloride (2.30 g, 43.09 mmol). The reaction mixture is stirred at room temperature for 20 hours, then cooled in refrigerator and the precipitate is remoiva by filtration. The mother liquor is concentrated to yield the crude product which is taken up in a limited amount of cold EtOH and the white precipitate is filtered. The beige filtrate is concentrated to yield p-methylbenzamidine hydrochloride as an off-white solid (7.15 g, 97%). 1H NMR (DMSOd6): δ 2.41 (s, 3H), 7.43 (d, 2H), 7.78 (d, 2H), 9.24-9.39 (broad d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][C:6]=1[C:7](=[O:8])[NH:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[S:15][CH:16]=1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1nc(CCNC(=O)c2cc(Cl)ccc2O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cl)cc1C(=O)NCCc1csc(C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-chloro-2-hydroxy-N-[2-(2-isopropyl-thiazol-4-yl)-ethyl]-benzamide (400 mg, 1.23 mmol, 1.00 eq.) and potassium carbonate anhydrous (340 mg, 2.46 mmol, 2.00 eq.) in acetone (20 mL), ethyl bromoacetate (0.14 mL, 1.29 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 5 hours. The reaction mixture was poured in water (50 mL). The mixture was extracted with AcOEt (2×20 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 45 fractions of 15 mL, Heptane+20% AcOEt to Heptane+80% AcOEt) to yield the ester as a white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@H:6]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:5]([CH3:20])([CH3:19])[CH2:4][CH2:3]1.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:1][C@H:2]2[CH2:3][CH2:4][C:5]([CH3:20])([CH3:19])[C@H:6]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])[CH2:7]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1N1C(=O)c2ccccc2C1=O
Yield: 114.8 %

Procedure:
To a solution of the cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (500 mg, 1.83 mmol) obtained in Example 590 in tetrahydrofuran (10 ml) were added 4-nitrobenzoic acid (321 mg, 1.05 mmol), triphenylphosphine (576 mg, 2.20 mmol) and a 40%-diethyl azodicarboxylate/toluene solution (1.00 ml, 2.20 mmol) at 3° C., and stirred overnight at room temperature. The reaction solution was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4,4-dimethylcyclohexyl 4-nitrobenzoate (509 mg, 66%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[C:16](\[CH3:22])/[C:17](OCC)=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12](/[CH:15]=[C:16](\[CH3:22])/[CH2:17][OH:18])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(=C\[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1)CO
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg (0.95 mmol) of enoate (138) in 2.0 mL of anhydrous tetrahydrofuran at 25° C. was added 18 mg (0.43 mmol) of lithium aluminum hydride and the resulting mixture was allowed to stir for 30 min.The reaction was quenched by the slow addition of saturated Rochelle's saltand diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with water and brine and then dried over MgSO4. Evaporation and flash chromatography (elution with 1:10 ethyl acetate-hexane) gave 220 mg of the allyic alcohol (139). 1H NMR (300MHz, CDCl3) δ 5.34 (d), 3.96 (d), 3.85 (m), 2.26-2.18 (m), 1.64 (d), 1.61-1.34 (m), 1.82 (s), 0.0 (s).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:10])=[O:9])[CH:5]([CH2:20][C:21]([OH:23])=O)[C:4](=[O:24])[NH:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C@H:59]1([NH2:68])[C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH2:61][CH2:60]1>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:25])[CH2:7][N:6]([S:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])(=[O:9])=[O:10])[CH:5]([CH2:20][C:21]([NH:68][CH:59]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH2:61][CH2:60]2)=[O:23])[C:4](=[O:24])[NH:3]1
Reactant: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)O)c(C)c1
Reactant: N[C@@H]1CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N2CC(C)(C)NC(=O)C2CC(=O)NC2CCc3ccccc32)c(C)c1
Reaction time: 0.03 h

Procedure:
[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)yl]-acetic acid (50 mg, 0.135 mmol) was dissolved in DMF (2.5 mL) and DIEA (0.1 mL) was added to make a solution. HATU (117 mg, 0.31 mmol) was added and after stirring for two min, (R)-(−)-indanamine (0.1 mL) was added and the mixture was stirred overnight. The solution was poured into EtOAc (50 mL), washed with saturated NH4Cl (1×50 mL), 1 N HCl (1×50 mL), saturated NaHCO3 (1×50 mL), and saturated brine (1×50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to provide a crude brown oil (140 mg). This crude oil was purified by SiO2 column chromatography (40 to 100% EtOAc in hexanes) to produce pure title compound. MS (APCI pos) 484 (M+H).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][C:33]([S:36](=[O:38])(=[O:37])[NH2:39])=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(S(N)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (400 mg, 1.02 mmol) is coupled to 4-bromobenzene-sulfonamide (241 mg, 1.02 mmol) using Method A. On filtration of the cooled reaction mixture through celite and removal of the solvents in vacuo, the crude residue obtained is used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].[C:43](OCC)(=[O:45])[CH3:44]>>[NH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:43](=[O:45])[CH3:44])[CH2:21][CH2:22]1)=[O:16])[C:36]([CH3:37])=[O:38]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Sc1ccccc1C(=O)N1CCN(CCOCCO)CC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1Sc1ccccc1C(=O)N1CCN(CCOCCOC(C)=O)CC1
Reaction time: 4 h

Procedure:
[2-(2-amino-phenylsulfanyl)-phenyl]-{4(2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methanone (10.7 g, 0.027 mol) was dissolved in ethyl acetate (50 ml) and triethylamine (7.4 ml) was added into reaction mixture. Acetic anhydride (7.6 ml, 0.081 mol) was slowly added to the reaction mixture at room temperature. After 4 h, the reaction mixture was evaporated to give a dark blue oil which was dissolved in ethyl acetate (50 ml) and washed with 2×25 ml saturated NaHCO3 solution and once with brine. The organic phase was evaporated to give a brown oil (10.9 g). The residue of [2-(2-acetamino-phenylsulfanyl)-phenyl-{4(2-(2-acetoxyethoxy)ethyl]-piperazin-1-yl}methanone was used further without purification.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]1[CH:33]=O>C1COCC1>[CH3:17][O:18][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:27](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:28][CH2:29][CH2:30][C:31]1=[O:32]
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1C=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/C1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.1 %

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.37 mmol) was added to a solution of dimethyl 2-oxoheptylphosphonate (87 mg, 0.33 mmol) in THF (2 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 1 h at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (crude from previous reaction, ˜0.37 mmol) in THF (2 mL) was added via cannula. The reaction was allowed to warm to rt. After 17 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 128 mg (95%) of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH:8]1[C:21]2[C:20](=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:18]1[C:19]2[C:20](=[C:22]3[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH2:24][CH2:23]3)[C:21]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)CCCBr
Reactant: c1ccc2c(c1)Oc1ccccc1C2=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)CCCN1CCC(=C2c3ccccc3Oc3ccccc32)CC1

Procedure:
7.2 g of 5-bromo-2-pentanone in 50 cc of chloroform are added dropwise to a suspension of 10.0 g of 4-(9-xanthenylidene)piperidine [M.P. 147°-149°, produced from N-methyl-4-(9-xanthenylidene)piperidine] and 9.25 g of sodium carbonate in 200 cc of chloroform. The reaction mixture is boiled at reflux for 17 hours, is filtered, concentrated by evaporation, the evaporation residue is placed on a column of 100 g of silica gel and elution is effected with chloroform containing 1% of methanol. The evaporation residue of the eluate is dissolved in acetone and made weakly acid to Congo red with hydrogen chloride in ether. The 5-[4-(9-xanthenylidene)piperidino]-2-pentanone hydrochloride which precipitates immediately is recrystallized from alcohol. M.P. 248°-251° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>C(O)C>[ClH:1].[ClH:1].[CH2:20]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: BrCCCCCCBr
Reactant: Clc1ccc2c(c1Cl)CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cl
Product: Clc1ccc2c(c1Cl)CN(CCCCCCN1CCc3ccc(Cl)c(Cl)c3C1)CC2
Reaction time: 36 h

Procedure:
A suspension of 2.38 g. (10 mmol) of 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline and 3.18 g. (30 mmol) of sodium carbonate in 50 ml. of absolute ethanol were refluxed for 5 minutes. To this suspension was added 1.22 g. (5 mmol) of 1,6-dibromohexane and the mixture refluxed overnight. The reaction was cooled and after standing for 36 hours was filtered of solid precipitate. The resulting solid was suspended in 100 ml. of ethyl acetate and treated with 1 g. of magnesium sulfate. The mixture was filtered and the filtrate treated with 10 ml. of ethereal hydrochloric acid. The resulting precipitate was removed by filtration, washed with ether and dried to give 2,2'-hexylene-bis(7,8-dichloro-1,2,3,4-tetrahydroisoquinoline)dihydrochloride having a melting point of 308°-311° C.