Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[CH3:36].[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[CH3:36][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:2]=1[NH:1][C:37](=[O:39])[CH3:38])[C:6]([N:8]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)c(C)c2)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(NC(C)=O)c(C)c2)c1
Yield: 89.2 %

Procedure:
Using 4-amino-3-methyl-N-{2-[4-(4-fluorobenzoyl)piperidino]-ethyl}-N-(3-methoxyphenyl)benzamide (489.0 mg, 1.00 mmol) and acetic anhydride (0.19 ml, 2.00 mmol), the procedure of Inventive Example 94 was repeated to obtain 474.0 mg (89.3%) of the title compound in a colorless amorphous form.
Reaction SMILES: [O:1]([C@@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@@H:15]2[CH3:17])[CH2:11][CH2:10]1)[Si](C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:1][C@H:9]1[C@@H:16]2[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[C@H:15]2[CH3:17])[CH2:11][CH2:10]1
Reactant: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a solution of 80G (11 mg, 0.026 mmol) in THF (1 mL) was added TBAF 1.0 M in THF, 0.26 mL). The reaction was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC (Phenomenex Luna 20×100 mm S5 C18, 10 min. grad, 20 mL/min, 20-100% B solvent, A=10% MeOH/water+0.1% TFA, B=90% MeOH/Water+0.1% TFA) to provide the title compound (5.1 mg): HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 2.40 min (100%); Chiral analytical HPLC (ChiralPak AD 4.6×250 mm, 20% IPA/hexane isocratic) retention time 18.6 min (100% ee); MS (ES) m/z 306.1 [M+H]+; HRMS calcd for C15H17ClN3O2 306.1009, Found 306.1010.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCO.[ClH:30]>[Fe].O>[ClH:30].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([S:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=3)=[CH:14][CH:13]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Nc1cc(Sc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2)ccn1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)Nc2ccc(Sc3ccnc(N)c3)cc2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
Nitro compound 10 (0.83 g, 2.07 mmol) was suspended in 2:1 EtOH:H2O (100 mL) and the resulting suspension brought to reflux. To this mixture was sequentially added Fe dust (0.54 g, 9.59 mmol) and c.HCl (2 mL), and the resulting dark orange suspension was refluxed for 1 h. After this time, the resulting yellow suspension was filtered hot through a pad of Celite, and the solvent removed under reduced pressure. The residue was re-suspended on H2O, to which was added a quantity of Celite, and the resulting suspension was stirred overnight. After this time, the suspension was filtered through a pad of Celite, and solvent was removed under reduced pressure to afford crude amine 11 as an amorphous off-white solid (0.65 g, 93%), which was used without further purification. 1H NMR [(CD3)2SO]: δ 9.98 (s, 1H, ArC(O)NHAr), 7.91 (ddd, J=9.40, 4.48, 2.58 Hz, 2H, ArH), 7.72 (m, 3H, ArH), 7.48 (ddd, J=9.37, 4.39, 2.55 Hz, 2H, ArH), 6.61 (d, J=7.85 Hz, 2H, ArH), 6.18 (dd, J=5.46, 1.68 Hz, 1H, ArH), 5.82 (d, J=1.36 Hz, 1H, ArH), 6.01 (br s, 2H, ArNH2), 5.82 (br s, 2H, ArNH2); HRMS: Calc. for C18H17N4OS (MH+) m/z 337.1123, found 337.1126.
Reaction SMILES: [C:1]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:2]([C:3]([O:5][CH:6]([CH3:7])[CH3:8])=[O:4])[C:1]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
A 250-mL round bottom flask was charged with diisopropyl malonate (2.09 g, 11.1 mmol) in DMF (24 mL). Sodium hydride (60% suspension, 0.44 g, 11.1 mmol) was slowly added to this solution at 0° C. After 15 minutes, a solution of 4-nitrobenzyl bromide (2.00 g, 9.26 mmol, 1.0 eq.) in DMF (24 mL) was added in one portion and then the reaction was stirred for 19 h. After this time, the reaction was warmed to rt. The reaction was quenched with 2N HCl then diluted in water (300 mL) and extracted with methyl tert-butylether (3×50 mL). The combined extract was washed with saturated sodium chloride (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with 9:1 hexanes/ethyl acetate to afford the title compound (2.02 g, 67%) as a colorless oil. MW=323.34. 1H NMR (DMSO-d6, 500 MHz) δ 8.15 (d, J=10.0 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 4.88 (septet, J=6.5 Hz, 2H), 3.89 (t, J=8.5 Hz, 1H), 3.19 (d, J=8.5 Hz, 2H), 1.14 (d, J=6.5 Hz, 6H), 1.11 (d, J=6.5 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1>C(O)(=O)C>[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][N:21]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(O)cc1
Temperature: 100 °C
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 174 mg of the title compound (85%) as a yellow solid in 99.8% purity by HPLC (Rt: 4.7, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Product: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
4-Bromo-2-nitrobenzoic acid piperidine amide. A suspension of 4-bromo-2-nitrobenzoic acid (0.60 g, 2.44 mmol) in thionyl chloride (8 mL) was heated to reflux for 2 h. The reaction mixture became homogeneous. The mixture was cooled and concentrated in vacuo to give 4-bromo-2-nitrobenzoyl chloride as a white solid, which was used immediately in the following reaction. 1H NMR (400 MHz, CDCl3): 8.20 (d, J=1.9 Hz, 1H), 7.92 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). To a solution of 4-bromo-2-nitrobenzoyl chloride (2.44 mmol) in DCM (15 mL) at ambient temperature was added piperidine (1.2 mL, 12.2 mmol). The reaction mixture was stirred for 3 h then poured into water and extracted with DCM (2×). The combined organic extracts were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford the title amide as a white solid (0.52 g, 76%). MS (ESI): m/z 313 [M+H]+. 1H NMR (400 MHz, CDCl3): (rotameric broadening) 8.33 (d, J=1.9 Hz, 1H), 7.82 (dd, J=8.1, 1.9 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 3.82–3.65 (bm, 2H), 3.16 (t, J=5.6 Hz, 2H), 1.90–1.35 (bm, 6H).
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:27][C:22]1[N:21]=[C:20]([N:16]2[CH2:15][CH2:14][CH:13]([N:2]([CH3:1])[C:3](=[O:12])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:18][CH2:17]2)[CH:25]=[C:24]([CH3:26])[N:23]=1
Reactant: Cc1cc(Cl)nc(C)n1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)nc(C)n1
Yield: 62 %

Procedure:
A mixture of benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (17.24 mmol, 1.0 eq.), 4-chloro-2,6-dimethylpyrimidine (2.94 g, 2068 mmol, 1.2 eq.) and K2CO3 (4.76 g, 34.48 mmol, 2.0 eq.) in acetone (80 ml) was refluxed for 14 hours. The mixture was concentrated, and the residue was taken up in water (150 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (150 ml) and sat. NaCl solution (150 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 70% ethyl acetate/hexane). Yield: 62% (3.8 g, 10.73 mmol)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][CH2:40][O:41][CH3:42].O>CN(C=O)C>[CH3:42][O:41][CH2:40][CH2:39][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=1)[CH2:11][NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:6]
Reactant: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cccc(O)c4)c3)ncnc12
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Temperature: 50 °C
Reaction time: 120 h

Procedure:
41 mg (0.1 mmol) 4-[3-(3-Hydroxy-benzoylamino)-benzylamino]-quinazoline-8-carboxylic acid amide were dissolved in 1 ml DMF. 97 mg (0.3 mmol) Cs2CO3 and 15 mg (0.11 mmol) 1-Bromo-2-methoxy-ethane were added. The mixture was stirred for 5 days at 50° C. Water was added to the reaction mixture, the percipitate was filtered and dried. 15.9 mg, off-white solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29]1>>[CH:28]1([CH2:31][C:32]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:33])[CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (48 mg, 73%), MS (ISP) m/z=413.5 [(M+H)+], mp 197.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-cyclopropyl-acetic acid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH2:20](Br)[CH:21]=[CH:22][CH3:23].CCCCCC>C1COCC1>[CH2:20]([CH:13]([C:12](=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:21]=[CH:22][CH3:23]
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=CCC(C(=O)OCC)C(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A 60% dispersion of NaH in mineral oil (917 mg, 22.9 mmol) was added over 20 min to a solution of ethyl 3-nitro-β-oxobenzenepropanoate (5.00 g, 21.1 mmol) in THF (50 mL) at such a rate to maintain a gentle reflux. The mixture was stirred at 25° for 30 min and a solution of crotyl bromide (2.95 g, 21.9 mmol) in THF (15 mL) was added over 50 min. The reaction mixture was stirred at 25° for 45 min and then heated at reflux for 16 h. Hexane (100 mL) was added to the cooled mixture. The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc and the resulting solution was washed with aqueous 10% citric acid (2×), aqueous saturated NaHCO3 (2×) and brine then was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (40-63μ silica gel, hexane:EtOAc, 9:1) to afford ethyl α-(2-butenyl)-3-nitro-β-oxobenzenepropanoate (4.60 g, 75% yield):
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=12.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>ClCCl>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:11][CH2:10][C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NCc1ccn2ccnc2c1
Solvent: ClCCl
Product: O=C(NCc1ccn2ccnc2c1)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of imidazo[1,2-a]pyridin-7-ylmethanamine (500 mg, 3.40 mmol) in dichloromethane (17 ml) at room temperature was added 1-bromo-4-isocyanatobenzene (680 mg, 3.40 mmol) as a single portion. The resulting suspension was stirred overnight and then filtered with dichloromethane washes to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Product: COc1cc(CO)ccn1
Temperature: 25 °C
Yield: 60 %

Procedure:
(2-Chloro-pyridin-4-yl)-methanol (2.82 g, 19.67 mmol) was refluxed with 25 wt. % sodium methoxide (25 ml) solution for 24 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (1:1)) to afford 1.8 g (60%) of (2-Methoxy-pyridin-4-yl)-methanol as a pale brown oil. 1H NMR (200 MHz, CDCl3) δ 2.16 (3H, s), 2.21 (3H, s), 5.13 (2H, s), 6.99 (1H, d, J=5.6 Hz), 8.11 (1H, br. s), 8.12 (1H, s), 8.23 (1H, d, J=5.6 Hz).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[Cl:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[C@@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)=[CH:17][CH:16]=1>>[Cl:12][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@:23]3([CH2:22][C@H:21]3[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[C:24]2=[O:32])=[CH:9][C:4]=1[C:3]([OH:2])=[O:13]
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cc(CBr)ccc1Cl
Product: O=C(O)c1cc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1 starting from 5-Bromomethyl-2-chloro-benzoic acid methyl ester (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H17Cl2NO3: 437, observed (M+H)+: 438.3. 1H NMR (400 MHz, DMSO-d6) δppm 2.07-2.15 (m, 1 H) 2.39 (dd, J=7.83, 5.05 Hz, 1H) 3.20 (t, J=8.72 Hz, 1 H) 5.06 (s, 2 H) 6.16 (d, J=7.58 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.97 (d, J=7.83 Hz, 1 H) 7.09 (t, J=7.83 Hz, 1 H) 7.28-7.40 (m, 4 H) 7.43-7.57 (m, 2 H) 7.73 (s, 1 H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][NH:23][CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:28])[F:27])[CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:27])[F:28])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To a solution of (4-(4-fluoro-2-(trifluoromethyl)phenyl) piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (38 mg, 0.088 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in DMF (2.0 mL) was added methanesulfonyl chloride (9 L, 0.12 mmol). The mixture was stirred for 16 h at ambient temperature. The solvent was removed under reduced pressure and the residue diluted with H2O (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% (10% CH30H in CH2Cl2 with 0.01% NH4OH) in CH2Cl2) and freeze dried to give (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone as a white solid (4 mg, 10%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.73-7.69 (m, 1H), 7.57-7.46 (m, 2H), 5.28-5.24 (m, 1H), 4.70-4.65 (m, 1H), 4.38-4.33 (m, 2H), 3.51-3.45 (m, 2H), 3.22-3.10 (m, 2H), 2.94 (s, 3H), 2.84-2.70 (m, 3H), 1.73 (br s, 4H); ESI MS m/z 475 [M+H]+.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:19][S:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])=[CH:34][CH:33]=3)[S:29][C:28]=2[CH:43]=1)(=[O:22])=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>>[ClH:1].[CH3:19][S:20]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[C:31]([C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:18][CH:17]=3)=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([O:38][S:39]([CH3:42])(=[O:40])=[O:41])=[CH:36][CH:37]=3)[S:29][C:28]=2[CH:43]=1)(=[O:21])=[O:22]
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Reaction time: 0.25 h

Procedure:
The acid chloride of 20.4 g. of 4-(2-pyrrolidinoethoxy)benzoic acid, hydrochloride was prepared as described in Example 1, and was used to acylate 20 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene as described in Example 1, except that the amount of aluminum chloride was 60 g., of which 30 g. was added initially, and the rest was added in 10 g. portions at 15 minute intervals. The reaction mixture was stirred for 16 hours, and was worked up as described in Example 1 to obtain an oil, which was crystallized from denatured ethanol to obtain 27.5 g. of purified product, m.p. 196°-199°. A 4 g. sample was purified further by chromatography to obtain an analytical sample, m.p. 207°-207.5°.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH3:8].[Cl:9][C:10]1[C:19]([I:20])=[CH:18][C:13]2[NH:14][C:15](=[S:17])[NH:16][C:12]=2[CH:11]=1>CC(C)=O>[Cl:9][C:10]1[C:19]([I:20])=[CH:18][C:13]2[N:14]=[C:15]([S:17][CH3:8])[NH:16][C:12]=2[CH:11]=1
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc2cc(I)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
K2CO3 (0.22 g, 1.61 mmol), followed by iodomethane (0.1 mL, 1.61 mmol), was added to a solution of 5-chloro-6-iodo-1,3-dihydro-2H-benzimidazole-2-thione (1 g, 3.22 mmol) in acetone (20 mL) at 0° C. The reaction was stirred at rt for 1 h. Additional K2CO3 (1.61 mmol) and iodomethane (1.61 mmol) were added. The reaction was stirred at rt overnight, then the volatiles were removed and the residue was partitioned between EtOAc and water. Concentration of the EtOAc layer afforded the desired product as a white foam, which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-phenyl-5-(1-hexenyl)pyridine (Example 15) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.40 (m, 3 H), 7.18 (m, 2 H), 4.33 (d, J=5 Hz, 2 H), 3.42 (septet, J=7 Hz, 1 H), 3.23 (septet, J=7 Hz, 1 H), 2.26 H), 1.31 (m, 13 H), 1.12 (m, 8 H), 0.80 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C24H35NO) 353, found 354 (M+H). Anal. Calcd for C24H35NO: C, 81.53; H, 9.98; N, 3.96. Found: C, 79.06; H, 9.65; N, 3.61. mp 71-72° C. Rf=0.1 (10% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][CH:8]([C:12](=O)[CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][NH2:30])[N:24]=1.O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[C:12]([CH3:13])=[N:30][N:29]([C:25]3[N:24]=[C:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=4)[CH:28]=[CH:27][N:26]=3)[C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: NNc1nccc(-c2ccccn2)n1
Reactant: CC(=O)C(SCc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1nn(-c2nccc(-c3ccccn3)n2)c(C)c1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
To a solution of 3-(4-chloro-benzylsulfanyl)-pentane-2,4-dione (1.15 g, 4.48 mmol) in ethanol (60 mL) was added (4-pyridin-2-yl-pyrimidin-2-yl)-hydrazine (0.838 g, 4.48 mmol) and p-toluenesulfonic acid monohydrate (ca. 20 mgs). The solution was heated to reflux and stirred for 5 hours. The reaction mixture was allowed to cool to room temperature, and water (200 mL) was added. The precipitate that formed was isolated by filtration and recrystallized from aqueous methanol to provide 1.36 g (74%) of the product as white needles: 1H NMR (CDCl3) δ 8.94-8.92 (m, 1H), 8.75-8.73 (m, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.28-8.26 (m, 1H), 7.91 (t, J=7.9 Hz, 1H), 7.46-7.43 (m, 1H), 7.20 (d, J=8.0 Hz, 2H), 6.89 (d, J=8.0 Hz, 2H), 3.66 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H) ppm. 13C NMR (CDCl3) δ 164.6, 160.5, 157.4, 155.2, 153.5, 149.8, 147.3, 137.6, 137.2, 133.1, 130.6, 128.7, 126.1, 122.2, 114.7, 111.3, 40.1, 14.2, 12.6 ppm.