Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1[CH:15]=[C:14]([Cl:16])[N:13]=[N:12][C:11]=1[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[Cl:16][C:14]1[N:13]=[N:12][C:11]([CH3:17])=[C:10]([O:8][C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: Nc1ncccc1O
Reactant: Cc1nnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnc(Cl)cc1Oc1cccnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
2-Aminopyridin-3-ol (5.0 g, 45.4 mmol) and 4,6-dichloro-3-methylpyridazine (7.4 g, 45.4 mmol, prepared according to WO 2003/041712) were dissolved in DMSO (100 mL). Cs2CO3 (16.3 g, 49.9 mmol) was added and the reaction stirred at ambient temperature for one hour. The reaction was diluted with water and the material was extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography followed by trituration of the concentrated solid with EtOH gave 3-(6-chloro-3-methylpyridazin-4-yloxy)pyridin-2-amine (5.98 g, 25.3 mmol, 55%) as a solid.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:1]2([C:10]([OH:12])=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][NH:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(O)C1NCc2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1(C(=O)Nc2ccc(Cl)cc2)NCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of (D,L) 2,3-dihydro-1H-isoindole-1-carboxylic acid (372 mg, 2.28 mmol) in 3N aq. NaOH (10 mL), a solution of 4-chlorophenylisocyanate (530 mg, 3.66 mmol) in dioxane (6 mL) was added. The mixture was stirred at room temperature overnight. It was then washed with Et2O (2×). The aqueous layer was separated, acidified with 4N HCl to pH 1 to 2. The product was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo to give the titled compound as a solid (550 mg), which was sufficiently pure to be used in the next reaction. MS 317.0 and 319.0 (M+H, Cl pattern).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:12]([NH:19][CH:8]1[CH2:9][CH2:10][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)N1CCC(NCc2ccccc2)CC1
Yield: 26.3 %

Procedure:
A solution of 1-tert-butyl-4-oxopiperidine (3.6 g, 23.1), benzylamine (5.1 ml, 46.8 mmol), acetic acid (1.5 ml) and sodium triacetoxyborohydride (7.38 g, 34.8 mmol) was stirred at ambient for 2 days. Reaction mixture reduced in vacuo, residue partitioned between aqueous K2CO3 and EtOAc. The organic portion was dried (Na2SO4), filtered and reduced in vacuo. The residue was subjected to chromatography using CH2Cl2/MeOH/NH4OH (87/12/1) as the eluent to yield N-benzyl-1-tert-butylpiperidin-4-amine (1.5 g) (LC/MS: Rt 0.45, [M+H]+ 247).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C:32]([F:34])([F:35])[F:33])[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(CC(F)(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cn(C(CC(F)(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
21 mg (38 μmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoyl}amino)benzoate (racemate) in 0.75 ml of methanol/water (4/1) were reacted with 25 mg (77 μmol) of caesium carbonate according to General Method 4. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 9 mg (46% of theory)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1.CO.[H][H]>[OH-].[OH-].[Pd+2].C(OCC)(=O)C>[CH3:19][O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2[nH]ccc2cc1O

Procedure:
5-(benzyloxy)-6-methoxy-1H-indole (3.00 g) was added to methanol (100 mL) and ethyl acetate (100 mL) in a pressure bottle. Palladium hydroxide on carbon (0.832 g) was added and the solution was shaken under 30 psi of hydrogen at room temperature for 40 minutes. The mixture was filtered through a nylon membrane, the solvent removed under vacuum, the residue taken up in ethyl acetate, the solution was filtered over a pad of silica gel, and the solvent was removed from the filtrate under vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11]([S:13](Cl)(=[O:15])=[O:14])[CH3:12]>CN(C)C=O.C(OCC)(=O)C>[CH2:11]([S:13]([N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1)(=[O:15])=[O:14])[CH3:12]
Reactant: CCS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)n1ccc([N+](=O)[O-])n1
Yield: 76.1 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (39 mg, 0.94 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the ethanesulfonyl chloride (94 μL, 1.00 mmol) was added. The mixture was continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 1-ethanesulfonyl-3-nitro-1H-pyrazole (139 mg, 77%) as a clear, waxy solid: H1-NMR (400 MHz, CDCl3) δ 1.38 (2H, t, J=7.2 Hz), 3.68 (2H, qt, J=7.2 Hz), 7.05 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].BrC1C=CC([N+]([O-])=O)=C(OC)C=1[F:27]>>[F:27][C:7]1[C:8]([O:13][CH3:14])=[C:9]([N+:10]([O-:12])=[O:11])[CH:2]=[CH:3][C:4]=1[C:5]#[N:6]
Reactant: COc1c([N+](=O)[O-])ccc(Br)c1F
Reactant: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])ccc(C#N)c1F

Procedure:
The title compound was prepared according to the procedure for 3-fluoro-5-methoxy-4-nitrobenzonitrile (Compound 146F) using 1-Bromo-2-fluoro-3-methoxy-4-nitrobenzene (Compound 147G). 1H NMR (CDCl3, 400 MHz): δ=4.15 (d, J=2.27 Hz, 3H), 7.45 (dd, J=8.59, 5.56 Hz, 1H), 7.64 (dd, J=8.59, 1.77 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])[CH:12]=[CH:13][C:14]=1/[CH:15]=[CH:16]/[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][S:25]([CH2:28][CH2:29][CH2:30][CH3:31])(=[O:27])=[O:26])=[C:20]([O:32][CH3:33])[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:28]([S:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:10][C:9]=2[OH:8])=[CH:19][C:20]=1[O:32][CH3:33])(=[O:27])=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCS(=O)(=O)Oc1ccc(C/C=C/c2ccc(/C=C/C(=O)OC)cc2OCc2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)cc2O)cc1OC
Yield: 86.1 %

Procedure:
11 g (20 mmol) of methyl(E)-3-(3-benzyloxy-4-{(E)-3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propenyl}phenyl)acrylate are dissolved in 100 ml of methanol and 1.1 g (10% massique) palladium-on-charcoal are then added. The reaction medium est placed under 1 atmosphere of hydrogen for 24 hours, and then filtered through Celite and rinsed with dichloromethane, and the filtration liquors are concentrated. The residue is purified by chromatography on a column of silica eluted with an 8/2 heptane/ethyl acetate mixture. 8 g (73%) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-hydroxyphenyl)propanoate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[SH:18]CCC(O)=O.[H-].[Na+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][SH:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: O=C(O)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CS)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
To a dimethylformamide (160 ml) solution of 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)oxirane (8.0 g) and methyl ester of 3-mercaptopropionic acid was added, under ice-cooling, 60% sodium hydride (4.0 g). The mixture was stirred for 15 minutes, to which was added dropwise a 1N aqueous solution of hydrochloric acid (101 ml) to adjust the pH to 7, followed by distilling off dimethylformamide and water. To the residue was added water (20 ml), which was extracted with ethyl acetate (50 ml×3). The extract was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was subjected to a silica gel chromatography (6.0×9.0 cm), followed by elution with ethyl acetate-hexane (3:1). The object fraction was concentrated, to which was added diethyl ether to afford 2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (6.44 g) as colorless needles, m.p. 112°-113° C.
Reaction SMILES: [C:1](OC1C2C(=CC=CC=2)N(CCC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)[C:28](=[O:42])[C:27]2=[O:43]>>[C:1]([O:43][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH2:34][CH2:35][N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)[C:28]1=[O:42])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: O=C(OC1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21)c1ccccc1

Procedure:
This compound was prepared in a similar way to 2-oxo-1-propylindolin-3-yl benzoate from 5-chloro-1-(3-morpholinopropyl)indoline-2,3-dione. 1H-NMR δ 8.07 (dd, 2H), 7.63 (dd, 1H), 7.53 (dd, 2H), 7.42 (s, 1H), 7.33 (dd, 1H), 7.6.92 (d, 1H), 6.09 (s, 1H), 3.84 (m, 2H), 3.76 (m, 4H), 2.50 (m, 6H), 1.97 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25](Br)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([C:34]3[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1
Reactant: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Br)cccc2[nH]1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(CCN5CCC(O)CC5)CC4)cc23)cn1

Procedure:
This compound is synthesized from compound 196 (see example 172) and (6-methoxy-pyridin-3-yl)-boronic acid analogously to the method described in Example 156.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:11]1[C@@H:7]2[C@@H:6]([CH2:10][CH2:9][CH2:8]2)[C:4]([OH:3])=[C:13]([C:14]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=3[S:16](=[O:29])(=[O:30])[N:15]=2)[C:12]1=[O:31]
Reactant: CCOC(=O)C1CCCC1N(CCN(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)CCN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2CCC[C@@H]21
Temperature: 60 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
A solution of 2-{(2-dimethylamino-ethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (25.4 mg, 0.047 mmol) in ethanol (2 mL) was treated with a 21% w/w solution of sodium ethoxide in ethanol (0.070 mL) and stirred for 2 h at 60° C. Glacial acetic acid (0.100 mL) was added, the solvents were removed in vacuo, and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-N-{3-[1-(2-dimethylamino-ethyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (5.7 mg, 0.011 mmol, 23.4%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.53-1.67 (3H, m), 2.02-2.19 (3H, m), 2.88 (6H, s), 3.07 (3H, s), 3.24-3.33 (2H, m), 3.38-3.45 (2H, m), 3.92-3.98 (1H, m), 4.08-4.15 (1H, m), 7.52-7.58 (3H, m), 9.27 (1H, s), 10.20 (1H, s). LC-MS (ESI) calcd for C20H27N5O6S2 497.14, found 498.3 [M+H+].
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(OC(=O)[NH:39][CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)(C)(C)C>>[NH2:39][CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH2:29][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=3[CH3:13])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:31])[CH:15]=2)[C:20](=[O:24])[N:19]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCN1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC[C@H]3CN)c2c1

Procedure:
The title compound was prepared according to the method of Example 81 using the product of Example 75 step i) and (S)-1-pyrrolidine-2-ylmethyl-carbamic acid tert-butyl ester hydrochloride. The product was purified using SCX ion-exchange chromatography (eluting with methanol followed by 3N ammonia in methanol), followed by HPLC.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>CSC.O1CCCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:6]2[CH2:5][CH2:4][CH:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2](=[O:1])[CH2:7]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)CC1CCC=CC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC(c2ccc(F)cc2)CC1=O
Reaction time: 0.33 h

Procedure:
This ester (4 g, 0.022 mmol), copper (I) bromide-dimethyl sulfide complex (4.88 g, 0.023 mmol) in dimethyl sulfide (20 ml) and tetrahydrofuran (120 ml) was cooled to −40° C. under nitrogen and treated dropwise with 4-fluorophenylmagnesium bromide (1M solution in THF, 43.9 ml) so that the temperature did not rise above −40° C. Reaction was stirred for 20 minutes before quenching with 1N HCl (300 ml) and extracting the products with ether (3×300 ml). Combined organic phase washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude oil was purified by silica chromatography eluting with hexane-ethyl acetate mixtures (10-20%), to give ethyl [4-(4-fluorophenyl)-2-oxo-cyclohexyl]acetate as a colourless oil, 2.8 g. 1H NMR δ (ppm) (CDCl3): 7.26-7.11 (2H, m), 7.04-6.94 (2H, m), 4.18-4.11 (2H, m), 3.55-3.44 (1H, m), 3.00-2.90 (1H, m), 2.80-2.73 (2H, m), 2.69-2.55 (1H, m), 2.28-2.17 (2H, m), 2.10-1.88 (2H, m), 1.61-1.42 (1H, m) and 1.31-1.25 (3H, m).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][Br:16])=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.0 g (20 mmol) of 4-benzoyltoluene and 3.6 g (20 mmol) of N-bromosuccinimide in 120 ml of carbon tetrachloride was added 0.05 g (0.2 mmol) of benzoyl peroxide. The reaction was refluxed for 17 hours, cooled to room temperature and filtered. The filtrate was evaporated and the crude product was taken on without further purification.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][O:7][CH2:8][C:9]([NH:26][C:27]([CH2:29][CH2:30][O:31][CH2:32][C:33]([NH:98][C:99]([CH2:101][CH2:102][CH2:103][NH:104][C:105](=[O:122])[O:106][CH2:107][C:108]1[C:109]2[C:114]([CH:115]=[C:116]3[C:121]=1[CH:120]=[CH:119][CH:118]=[CH:117]3)=[CH:113][CH:112]=[CH:111][CH:110]=2)=[O:100])([CH2:66][O:67][CH2:68][CH2:69][C:70]([NH:72][C:73]([CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96]C)=[O:95])([CH2:82][O:83][CH2:84][CH2:85][C:86]([O:88]C)=[O:87])[CH2:74][O:75][CH2:76][CH2:77][C:78]([O:80]C)=[O:79])=[O:71])[CH2:34][O:35][CH2:36][CH2:37][C:38]([NH:40][C:41]([CH2:58][O:59][CH2:60][CH2:61][C:62]([O:64]C)=[O:63])([CH2:50][O:51][CH2:52][CH2:53][C:54]([O:56]C)=[O:55])[CH2:42][O:43][CH2:44][CH2:45][C:46]([O:48]C)=[O:47])=[O:39])=[O:28])([CH2:18][O:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[O:4]>CC(C)=O.[OH-].[Na+]>[C:46]([CH2:45][CH2:44][O:43][CH2:42][C:41]([NH:40][C:38]([CH2:37][CH2:36][O:35][CH2:34][C:33]([NH:98][C:99]([CH2:101][CH2:102][CH2:103][NH:104][C:105](=[O:122])[O:106][CH2:107][C:108]1[C:109]2[C:114]([CH:115]=[C:116]3[C:121]=1[CH:120]=[CH:119][CH:118]=[CH:117]3)=[CH:113][CH:112]=[CH:111][CH:110]=2)=[O:100])([CH2:32][O:31][CH2:30][CH2:29][C:27]([NH:26][C:9]([CH2:10][O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([CH2:8][O:7][CH2:6][CH2:5][C:3]([OH:4])=[O:2])[CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:28])[CH2:66][O:67][CH2:68][CH2:69][C:70]([NH:72][C:73]([CH2:82][O:83][CH2:84][CH2:85][C:86]([OH:88])=[O:87])([CH2:74][O:75][CH2:76][CH2:77][C:78]([OH:80])=[O:79])[CH2:90][O:91][CH2:92][CH2:93][C:94]([OH:96])=[O:95])=[O:71])=[O:39])([CH2:58][O:59][CH2:60][CH2:61][C:62]([OH:64])=[O:63])[CH2:50][O:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])([OH:48])=[O:47]
Reactant: COC(=O)CCOCC(COCCC(=O)OC)(COCCC(=O)OC)NC(=O)CCOCC(COCCC(=O)NC(COCCC(=O)OC)(COCCC(=O)OC)COCCC(=O)OC)(COCCC(=O)NC(COCCC(=O)OC)(COCCC(=O)OC)COCCC(=O)OC)NC(=O)CCCNC(=O)OCc1c2ccccc2cc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)CCOCC(COCCC(=O)O)(COCCC(=O)O)NC(=O)CCOCC(COCCC(=O)NC(COCCC(=O)O)(COCCC(=O)O)COCCC(=O)O)(COCCC(=O)NC(COCCC(=O)O)(COCCC(=O)O)COCCC(=O)O)NC(=O)CCCNC(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
9-Anthrylmethyl N-[({tris[(2-{[(tris{[2-(methoxycarbonyl)ethoxy]methyl}methyl)amino]carbonyl} ethoxy)methyl]methyl}amino)carbonyl]propylcarbamate (0.60 g, 0.34 mmol) was dissolved in acetone (30 ml) and 0.20 N NaOH (30 ml). After stirring at room temperature for 1 d, the acetone was evaporated. The aqueous solution was washed with EA, stirred in an ice bath and acidified with dilute HCl. After the product was extracted with EA, the organic solution was dried with anhydrous MgSO4, filtered and evaporated. The total weight of the final yellow powder was 0.37 g and the yield was 68%.
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:13][CH2:12][N:11](CC3C=CC=CC=3)[CH:10]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][CH:24]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[C:2]1([N:8]2[CH2:13][CH2:12][NH:11][CH:10]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:25][CH:24]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(NCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(NCC2CN(c3ccccc3)CCN2)cc1

Procedure:
In a manner similar to Example 1, react N-[4-[[[4-phenyl-1-(phenylmethyl)piperazin-2-yl]methyl]amino]phenyl]methanesulfonamide hydrochloride (2.05 g, 4.22 mmol) with H2 over 10% palladium on activated carbon (0.19 g). Remove the catalyst by filtration and evaporate the solvent. Dissolve the residue in methanol and adjust the pH to 8 with 4M aqueous NaOH. Remove the solvent in vacuo. Triturate the residue with methylene chloride. Remove the solid by filtration. Recrystallize the residue from methylene chloride to obtain the title compound.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:24])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].S(OC)(O[CH3:31])(=O)=O>C1COCC1.CN(C=O)C>[C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([O:24][CH3:31])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-2H-pyrazol-3-ol (0.29 g, 0.88 mmol) and sodium hydride (50 mg, 1.25 mmol of a 40% suspension in mineral oil) were stirred in THF-DMF (1:1) (10 mL) at 0° C. for 0.5 h, then allowed to warm to room temperature. Dimethyl sulphate (0.1 mL, 1 mmol) was added and the mixture stirred overnight. After concentration in vacuo, the mixture was poured into water (10 mL) and extracted with EtOAc (20 mL). The organic layer was separated washed with water (2×10 mL) and dried (MgSO4). Filtration and evaporation of the solvent afforded a yellow oil, which was purified by chromatography with EtOAc-hexane (1:1) as eluant. (0.24 g, 81%).