Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[CH:11]=[N:10]1.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([SH:38])[CH:33]=1.CCCCP(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=[CH:11][C:12]=3[CH:26]([CH3:27])[CH3:28])=[CH:17][C:18]=2[CH3:25])[CH3:23])[CH:33]=1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)O
Reactant: COC(=O)c1cccc(S)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(SC(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)c1
Temperature: 0 °C
Yield: 53.4 %

Procedure:
To an ambient temperature solution of 1-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethanol (75 mg, 1.78 mmol) in toluene (20 mL) are added 3-Mercapto-benzoic acid methyl ester (299 mg, 1.78 mmol) and tri-N-butylphosphine (668 μL, 2.68 mmol). The reaction mixture is cooled to 0° C. 1,1′-(Azocarbonyl)-dipiperidine (676 mg, 2.68 mmol) is added and the reaction mixture is warmed to room temperature overnight. The reaction mixture is concentrated and the residue is chromatographed (40 g SiO2, 0% to 30% EtOAc/Hexanes) to yield the title compound (541 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 8.00-7.98 (m, 1H), 7.99 (t, 1H, J=1.8 Hz), 7.87 (dt, 1H, J=4.6, 2.5 Hz), 7.70 (s, 1H), 7.43-7.39 (m, 3H), 7.32-7.22 (m, 3H), 6.61-6.54 (m, 2H), 4.79 (s, 2H), 4.53 (q, 1H, J=7.0 Hz), 3.90 (s, 3H), 2.99 (sept, 1H, J=6.6 Hz), 2.32 (s, 3H), 1.56 (d, 3H, J=6.9 Hz), 1.30 (d, 6H, J=6.6 Hz).
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:38][C:39]([NH:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:50]=2)[CH:45]=[CH:44][CH:43]=1)=[O:40]>C(#N)C>[CH3:56][S:53]([O:52][C:49]1[CH:50]=[C:51]2[C:46]([CH:45]=[CH:44][CH:43]=[C:42]2[NH:41][C:39](=[O:40])[CH2:38][NH:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=2)=[CH:47][CH:48]=1)(=[O:55])=[O:54]
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CNCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B (25.6 g, 72.7 mmol) in 200 mL of acetonitrile was added diisopropylethylamine (50 mL, 303 mmol), followed by the product from Step D (19.0 g, 60.5 mmol). The reaction was stirred at room temperature overnight, then concentrated in vacuo. The resulting material was partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: C([O:4][C:5]([C:7]1([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])(C)C.[OH-].[K+].OS(O)(=O)=O>C(O)CO>[CH2:17]([CH:14]([CH2:15][CH3:16])[CH2:13][C:7]1([C:5]([OH:6])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)[CH3:18]
Reactant: CCC(CC)CC1(C(=O)OC(C)C)CCCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 160 °C
Reaction time: 42 h
Yield: 59.9 %

Procedure:
1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid isopropyl ester (3.0 g, 11.8 mmol) was dissolved in ethylene glycol (48 mL). Powdered KOH (6.0 g, 107 mmol) was added and the mixture was stirred 42 h at 160° C. The cooled reaction mixture was slowly added to a stirred mixture of ice-water (120 mL) and 4M H2SO4 (40 mL), and extracted with DCM (2×120 mL). The organic phases were washed with diluted aq. NaCl until neutral, combined, dried over sodium sulfate and concentrated. The residue (2.5 g) was taken up in 4N NaOH and ice (30 g). The alkaline solution (pH 12) was extracted with TBME (40 mL). The TBME phase was washed twice with 4N NaOH/ice. The basic aqueous phases were made acidic to pH 1 using aq. H2SO4. Extraction with DCM (2×50 mL), washing with diluted aq. NaCl, drying over sodium sulfate and evaporation afforded 1.5 g (60%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 94.1% (GC area, after derivatization with diazomethane).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:15][C@H:16]([C:24](O)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:11]([O:10][C:8](=[O:9])[NH:15][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:25])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OC1CCNCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (75 mmol) and Boc-L-phenylalanine (38 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 144 hour reaction time) and the product used without further purification. Yield 12.2 g, 96%; HPLC (60/40) 3.45 minutes (97%).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([C:23](Cl)=[O:24])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>>[CH2:2]([NH:4][C:23]([C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][Br:5])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:24])[CH3:3]
Reactant: CCN
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Product: CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from ethylamine hydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2ccccn2)c1F
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccccn4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(2-fluoro-3-(pyridin-2-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.57 (6H, s), 7.62 (1H, dd, J 7 and 5), 7.64 (1H, s), 7.80-7.85 (1H, m), 7.89 (1H, d, J 7), 8.03 (1H, s), 8.10-8.19 (2H, m), 8.62 (1H, s), 8.83 (1H, d, J 5), 9.35 (1H, dd, J 7 and 3); m/z (ES+) 349 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].Cl[C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:10]1[C:15]2[O:16][CH2:17][CH2:18][N:19]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[C:14]=2[N:13]=[CH:12][N:11]=1
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: Nc1ccncc1Cl
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Nc4ccncc4Cl)ncnc32)CC1

Procedure:
By the procedure described in Example 3, with the exception that 3-chloro-4-aminopyridine was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A was converted into Example 120. 1H NMR (500 MHz, CDCl3) δ ppm 1.24 (d, J=6.60 Hz, 6H) 1.59-1.64 (m, 2H) 1.66-1.74 (m, 2 H) 2.85-2.93 (m, 2H) 3.44-3.47 (m, 2H) 4.25-4.29 (m, 4H) 4.80-4.87 (m, 1H) 4.87-4.94 (m, 1H) 7.60 (s, 1H) 8.09 (s, 1H) 8.31 (d, J=6.05 Hz, 1H) 8.44 (s, 1H) 8.75 (d, J=5.50 Hz, 1H). LRMS (ESI): 433.3/435.2 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]2[C:20]3[N:21]=[C:22]([Cl:25])[N:23]=[CH:24][C:19]=3[N:18]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:17]=2)(O)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]2[C:20]3[N:21]=[C:22]([Cl:25])[N:23]=[CH:24][C:19]=3[N:18]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:17]=2)=[CH:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cnc(Cl)nc23)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cnc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A solution of 4-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)cyclohex-anol (1.00 g, 1.6 mmol) in CH2Cl2 (20 mL) was added MsCl (275 mg, 2.4 mmol) followed by NEt3 (808 mg, 8 mmol). The reaction mixture was stirred at room temperature for 6 hours, quenched with brine and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (485 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.34 (s, 1H), 7.25-7.21 (m, 9H), 7.08-7.05 (m, 6H), 6.89 (s, 1H), 3.90-3.86 (m, 1H), 2.49-2.43 (m, 1H), 2.37-2.28 (m, 1H), 2.19-2.13 (m, 1H), 1.85-1.82 (m, 1H), 1.68-1.62 (m, 2H), 0.82 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (276 mg, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:18]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][Br:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (4-(benzyloxy)phenyl)methanol (21.4 g, 100 mmol) in diethyl ether (250 mL) at 0° C. was added phosphorous tribromide (10.8 g, 40 mmol) and stirred at 0° C. for 30 minutes and at room temperature for 3 hours. The reaction was quenched with water and the layers were separated. The organic layer was washed with water (2×400 mL), saturated sodium bicarbonate (2×400 mL), and brine. The ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-(benzyloxy)-4-(bromomethyl)benzene (746).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[N:11]([CH2:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=3)=[O:26])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)n[nH]c2=O)cc1
Reactant: O=C(CCl)NCc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(CC(=O)NCc3cccc(C(F)(F)F)c3)c2=O)cc1

Procedure:
1.00 g (3.17 mmol) of 5-(4-chlorophenyl)-4-(4-methoxyphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 55A, 0.80 g (3.17 mmol) of 2-chloro-N-[3-(trifluoromethyl)phenylmethyl]-acetamide and 0.88 g (6.33 mmol) of potassium carbonate are suspended in 20 ml of acetonitrile and heated under reflux for 8 hrs. The mixture is then concentrated in vacuo, and the residue taken up in water and extracted three times with ethyl acetate. The combined organic phases are concentrated and the residue purified by preparative HPLC [Method 12]. 1.07 g (64% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-4-piperidone (7.2 g, 39.64 mmol), and pyrrolidine (4.23 g, 59.5 mmol) in toluene (50 mL) is refluxed for 4 hr with a Dean-Stark trap to remove water. The mixture is cooled to rt and removal of solvent in vacuo provides the title compound as a light orange oil, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[O:23][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([N:15]([CH2:17][C@@H:18]([N:20]=[N+]=[N-])[CH3:19])[N:14]=[CH:13]3)=[C:8]2[CH2:7]1)=[O:5])[CH3:2].Cl>CO.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[O:23][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([N:15]([CH2:17][C@@H:18]([NH2:20])[CH3:19])[N:14]=[CH:13]3)=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(ccc3cnn(C[C@H](C)N=[N+]=[N-])c23)O1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C1Cc2c(ccc3cnn(C[C@H](C)N)c23)O1
Yield: 25.3 %

Procedure:
To a solution of the product from Step A (0.13 g, 0.41 mmol) in methanol (20 mL) was added palladium-on-carbon (10%, 0.015 g). This mixture was stirred overnight under an atmosphere of hydrogen (0.4 mL of a 2 N HCl in ethanol was added to protect the ethyl ester). The reaction mixture was filtered and purified by reversed phase HPLC (gradient of acetonitrile in water, 0% to 50% with 0.1% trifluoroacetic acid). The desired fractions were combined, concentrated, treated with 2 N HCl in ethanol (10 mL) and evaporated to a residue which was dried under high vacuum at 78° C. overnight to afford an amorphous solid (0.03 g, 20%): LC/MS (+APCI) m/z 290 (M+H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][C:21](Cl)=[N+:22]([O-:24])[CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CCCCO>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][C:21]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[N+:22]([O-:24])[CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(Cl)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: CCCCO
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To the solution of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-oxide (5.1 g, 9.62 mmol) in 80 mL of n-BuOH was added N-methylpiperazine (7.41 g, 74.1 mmol) under N2 atmosphere. Then the solution was stirred at 80° C. overnight. Concentrated and purified by flash chromatography to afford 4.98 g 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-(4-methylpiperazin-1-yl)-4-(o-tolyl)pyridine 1-oxide as a white solid (Yield: 87.2%). 1HNMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 7.93 (s, 1H), 7.78 (s, 2H), 7.38 (m, 2H), 7.28 (m, 1H), 7.17 (m, 1H), 7.07 (s, 1H), 5.50 (s, 3H), 2.72 (d, J=4.4 Hz, 4H), 2.57 (m, 3H), 2.40 (s, 3H), 2.23 (s, 3H), 1.45-1.20 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1CCCCC1Cl
Solvent: CCOCC
Product: O=C1CCCCC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A solution of 4-chlorophenylmagnesium bromide (200 mL of 1 M in ether, 200 mmol) was cooled in an ice-bath and a solution of 2-chlorocyclohexanone (26.5 g, 200 mmol) in 200 mL of ether was slowly added. The mixture was stirred at room temperature for 4 hours and was then concentrated under reduced pressure. Benzene (300 mL) was added and the mixture was heated under reflux for 12 h. Dilute aqueous HCl was added and the organic layer was separated, washed with brine, dried (sodium sulfate) and evaporated. Bulb-to-bulb distillation (2 mm) afforded 30.8 g of liquid product that subsequently crystallized.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[Cl:28][C:29]1[CH:30]=C([CH:34]=[CH:35][CH:36]=1)CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:34]=[CH:35][CH:36]=[C:29]([Cl:28])[CH:30]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Cl)c1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: O=C(OCc1cccc(Cl)c1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 48 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 14.2 g of 3-chlorobenzyl alcohol is stirred at 130° for 48 hours, the mixture is diluted with about 20 ml of methylene chloride and chromatographed on about 300 g of silica gel while eluting with ethyl acetate. By crystallization from ethyl acetate and hexane there is obtained m-chlorobenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 114°-116°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.CCOC(C)=O>[N:36]1([C:21]2[CH:20]=[C:19]([C:17]3[S:18][C:14]4[C:13]([C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=5)=[C:12]([C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:27]([CH3:28])=[CH:26][C:15]=4[N:16]=3)[CH:24]=[CH:23][N:22]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 160 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30 mg, 0.057 mmol) and 1H-indazole (6.0 mg, 0.052 mmol) in DMF (0.5 mL) was added K2CO3 (16.0 mg, 0.117 mmol) and 18-crown-6 (0.1 mg, 5.1×10−4 mmol). The reaction mixture was heated in a microwave at 160° C. for 1 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 60% ethyl acetate/hexanes) and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O3S: 611.2; found: 611.3.
Reaction SMILES: B.O1CCCC1.Cl.C([C:11]1([CH2:24][C:25]([O:27][CH2:28]C)=[O:26])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(O)=O.CO>O1CCCC1>[C:18]1([CH2:17][N:14]2[CH2:13][CH2:12][C:11]3([CH2:28][O:27][C:25](=[O:26])[CH2:24]3)[CH2:16][CH2:15]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC1(C(=O)O)CCN(Cc2ccccc2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.2 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 60 mL, 60 mmol) was added to a suspension of α-ethyl 4-carboxy-1-(phenylmethyl)-4-piperidineacetate hydrochloride (Helv. Chim. Acta 1972, 55, 2432–2438, 10.24 g, 30 mmol) in tetrahydrofuran (150 mL) and the mixture was stirred at room temperature for 3 days. Further borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 60 mL, 60 mmol) was added and the mixture was stirred at room temperature for 1 day. Methanol (20 mL) was added and the solvent was evaporated under reduced pressure. Methanol (200 mL) was added and the solvent was evaporated under reduced pressure. Methanol (200 mL) was added and the solvent was evaporated under reduced pressure. Hydrochloric acid (2M, 200 mL) was added and the mixture was heated under reflux for 4 hours. The mixture was cooled. Ether (200 mL) was added and the layers were separated. The organic layer was extracted with hydrochloric acid (2M, 2×100 mL) and the combined aqueous fractions were washed with ether (2×100 mL), adjusted to pH 10 with saturated aqueous potassium carbonate and extracted with dichloromethane (3×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(aq.) (96:4:0.4), to give the title compound (3.4 g, 46%). m/z (ES+) 246 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([SH:8])[CH:7]=1.Cl[C:14]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([S:8][C:14]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:15]=2[C:16]#[N:17])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(Cl)c(C#N)c1
Reactant: O=C(O)Cc1cc(S)cc(Cl)c1
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)cc(CC(=O)O)c2)c(C#N)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from step (i) and the product from example 12 step (i).