Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]=[CH:33][C:34]([O:36]C)=[O:35])[CH:25]=1.[H-].[Na+].Cl>C1COCC1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:24]2[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]=[CH:33][C:34]([OH:36])=[O:35])[CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20]
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)C=Cc1cc(Cl)nc(OC)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(OC)n3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (480 mg) and methyl 3-(6-chloro-2-methoxypyrimidin-4-yl)acrylate (360 mg) in THF (8.0 mL) was added 60% sodium hydride (128 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (520 mg) as a white solid.
Reaction SMILES: C(O)(=O)C.OO.[Cl:7][C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH3:19])=[C:12]2[C:17]=1S[CH2:15][CH2:14][C:13]2=[O:18].[S:25]([O-:28])(O)=[O:26].[Na+]>O>[Cl:7][C:8]1[CH:9]=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:11]([CH3:19])=[C:12]2[C:17]=1[S:25](=[O:28])(=[O:26])[CH2:15][CH2:14][C:13]2=[O:18]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2(=O)=O
Yield: 54 %

Procedure:
3 Milliliters of acetic acid and 1.75 g (15.47 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 2.00 g (7.03 mmol) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one in a 50-ml round-bottomed flask, and the mixture was allowed to react at 70° C. for 2 hours. The reaction mixture was diluted with about 50 ml of water, and a sodium hydrogensulfite was added to decompose excess hydrogen peroxide. Then, the mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to give 1.20 g (yield 54%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one-1,1-dioxide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.Cl.[NH2:17][C@@H:18]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: O=C(O)c1ccc(-c2nccs2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(-c3nccs3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1,3-thiazol-2-yl)benzoic acid (110 mg, 0.6 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (220 mg, 0.6 mmol), and HATU (210 mg, 0.6 mmol) stirring in methylene chloride (5 mL) is added N,N-diisopropylethylamine (340 μL, 1.9 mmol). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is partitioned between methylene chloride and water. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, gradient 95:5 to 92:8 methylene chloride/methanol) provides the title compound. ESI MS m/z 522.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:8][C:6]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(F)cc1C
Product: CCOC(=O)c1ccc(F)cc1CBr

Procedure:
Reaction of ethyl 5-fluoro-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-5-fluoro-o-toluate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11](S(C)(=O)=O)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][O:6][C:7]1[N:12]=[C:11]([N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])[N:8]=1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CCNCC
Product: CCN(CC)c1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(3,4-Difluorobenzyloxy)-4-(methylsulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-pyrimidine (Reference Example 7) (29 mg, 0.05 mmol) was reacted with diethylamine (38.0 mg, 0.52 mmol) by the same general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=548 (M++1); Rt=3.84 min. 1H-NMR 400 MHz (CDCl3): δ 0.96-1.00 (m, 6H), 3.20-3.30 (m, 4H), 5.30-5.40 (m, 2H), 6.90 (d, J=9 Hz, 1H), 7.01-7.21 (m, 8H), 7.35-7.40 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:34])[F:35])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (521 mg, 2.8 mmol) in DCM (6 ml) was added NEt3 (547 μl, 3.92 mmol, 1.4 eq.) and 4-trifluoromethoxy-benzenesulfonyl chloride (880 mg, 3.36 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 12 hrs. The excess of sulfonyl chloride was quenched by addition of trisamine resin (150 mg), and subsequent stirring for 2 hrs. The resin was then filtered off, and NaHCO3 sat (5 ml) was added. Filtration of the resulting mixture through hydrophobic catridge and subsequent removal of the solvent under reduced pressure afforded the desired 4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH3:26][NH:27][CH2:28][C:29]#[CH:30].CC#N>O>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:27]([CH3:26])[CH2:28][C:29]#[CH:30])[CH2:5][CH2:4]1
Reactant: C#CCNC
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: O
Product: C#CCN(C)c1cc(NC)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.158 mmol), N-methyl-propargylamine (79 μL, 0.95 mmol) and MeCN (10 mL) is irradiated in a microwave oven for 45 min at 160° C., and after cooling diluted with water. The mixture is extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]1[CH2:24]O.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]1[CH2:24][N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 17, 2'-chloro-5-nitro-2-[5-methyl-2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-5-nitro-2-[5-methyl-2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([O:36]CC1C=CC=CC=1)=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([S:8]([NH:11][C@@H:12]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:29])[NH:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=1)(=[O:21])=[O:20])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)NCC(=O)O)cc1
Yield: 95.4 %

Procedure:
The compound of Example 10 (300 mg, 0.47 mmol) was dissolved in 10 mL of MeOH and then 10% Pd/C (150 mg) was added. The reaction was hydrogenated under normal pressure overnight, filtered through Celite, rinsed with MeOH (3×10 mL) and concentrated in vacuo to give the desired compound (242 mg, 84%) which was used without further purification. ES-MS (M+H)+540.0
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1.CCN(C(C)C)C(C)C>>[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC1(C)CCCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 120 °C
Yield: 14 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 110 mg, 0.390 mmol), 2,2-dimethylpiperidine hydrochloride (117 mg, 0.779 mmol, Anichem, North Brunswick, N.J.), and DIPEA (339 μl, 1.948 mmol), heating at 120° C. for 5 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided 2-(3-(2,2-dimethylpiperidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (14% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (s, 6H) 1.61-1.82 (m, 6H) 2.87 (t, J=6.85 Hz, 2H) 3.45 (td, J=6.80, 2.45 Hz, 2H) 3.61-3.66 (m, 2H) 6.96 (br. s., 1H) 7.09 (d, J=2.35 Hz, 1H) 7.52 (t, J=7.82 Hz, 1H) 7.73 (dd, J=8.12, 1.27 Hz, 1H) 7.93 (dd, J=7.43, 1.37 Hz, 1H) 8.78 (s, 1H) 11.76 (br. s., 1H). MS (ESI, pos. ion) m/z: 376.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)[CH:18]=[CH2:17]
Reactant: Oc1ccc2c(c1)CCS2
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCS2
Yield: 83.3 %

Procedure:
To a solution of 5-hydroxy-2,3-dihydrobenzothiophene (1.53 g, 10.05 mmoles) in 200 mL acetone was added K2CO3 (12.5 g, 90.45 mmoles) with good mechanical stirring. The suspension was warmed and allyl bromide (4.86 g, 40.20 mmoles) was added in one portion. The reaction mixture was then heated to reflux overnight. After cooling, the solids were removed by filtration and the filtrate concentrated. The residue was taken up in 50/50 vol/vol hexane/methylene chloride and refiltered to remove the remaining salts. Concentration afforded 3.2 q crude product (a yellow oil) which was purified by flash chromatography (3% EtOAc in hexane to elute) to give 1.61 g pure product (83.4%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:13])[CH:3]=1
Reactant: COC(=O)c1cc(I)c(N)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(N)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of compound 70n (0.642 mmol, 200 mg), CuI (0.064 mmol, 12.2 mg) and Pd(PPh3)2Cl2 (0.064 mmol, 45 mg) in THF (2 mL) was added ethynyltrimethylsilane (0.963 mmol, 95 mg) followed by Et3N (7.19 mmol, 1 mL) under N2. The reaction mixture was stirred at room temperature for 1.5 h and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 70p.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:34]#[N:35])=[CH:7][N:6]=1)(=O)=O.[NH2:36][CH:37]([C:39]1[CH:40]=[CH:41][C:42]([C:45]2([OH:52])[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)=[N:43][CH:44]=1)[CH3:38].[OH-].[Li+]>O1CCCC1>[OH:52][C:45]1([C:42]2[N:43]=[CH:44][C:39]([CH:37]([NH:36][C:5]3[N:10]=[C:9]([C:11]4[C:19]5[C:14](=[N:15][CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=5)[NH:13][CH:12]=4)[C:8]([C:34]#[N:35])=[CH:7][N:6]=3)[CH3:38])=[CH:40][CH:41]=2)[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]1
Reactant: CC(N)c1ccc(C2(O)CCN(C)CC2)nc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Nc1ncc(C#N)c(-c2c[nH]c3ncc(C(F)(F)F)cc23)n1)c1ccc(C2(O)CCN(C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
2-(Methylsulfonyl)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (160.2 mg, 0.255 mmol) was added to a solution of 4-(5-(1-aminoethyl)pyridin-2-yl)-1-methylpiperidin-4-ol (66.01 mg, 0.28 mmol) in tetrahydrofuran (8 mL). The reaction mixture was stirred under nitrogen at room temperature for 18 hours. 1M Lithium hydroxide (1.020 mL of 1 M, 1.020 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (12.5 mg, 9% yield).
Reaction SMILES: CN(C=O)C.CS(O[CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:36][C:23]([F:35])([C:24]1([OH:34])[CH2:25][C:26]([CH3:32])([CH3:33])[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][N:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]2=[O:44])[O:16][N:15]=1)=[O:37]
Reactant: Oc1ccccn1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(Cn3ccccc3=O)on2)C1
Temperature: 50 °C
Yield: 53.4 %

Procedure:
To a DMF (1.0 mL) solution of the compound (30 mg) obtained in Example 3-(5) and pyridin-2-ol (12 mg), K2CO3 (35 mg) was added and the mixture was stirred at 50° C. for an hour. To the reaction mixture, DMSO (1.0 ml) was added and after filtering off the insoluble matter, the filtrate was purified by reverse-phase preparative HPLC to give Compound 54 (2.0 mg, colorless oil) and Compound 60 (16.0 mg, colorless oil.)
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17])(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH3:35])[CH:28]=[C:29]([O:33]C)[C:30]=1[O:31][CH3:32].CO>ClCCCl>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:28]1[C:29]([OH:33])=[C:30]([O:31][CH3:32])[C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH3:35])=[O:17]
Reactant: CC(=O)OCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc(C)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CO
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of 12-acetoxy-n-dodecanoyl chloride (8.5 g) in 1,2-dichloroethane (30 ml) is added aluminum chloride (8.2 g) and the mixture is stirred at room temperature for 2 hours. The mixture is cooled to 5° C. and a solution of 3,4,5-trimethoxytoluene (5.6 g) in 1,2-dichloromethane (20 ml) is added to the above mixture. The mixture is stirred at room temperature for 72 hours, and at 50° C.-60° C. for 30 minutes. Methanol (200 ml) is added to the reaction mixture and the mixture is stirred at 50° C. for 3 hours. The solvent is distilled off, and the residue is subjected to extraction with dichloromethane. The dichloromethane layer is washed with water and dried over magnesium sulfate. The solvent is distilled off to thereby leave crude crystals. The product is recrystallized from ether-hexane (1:1) to give 6-(12-hydroxy-1-oxododecyl)-2,3-dimethoxy-5-methylphenol (8.5 g) as colorless needles. Melting point 82° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:35]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:12]2[NH:35][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (525 mg) in acetic acid (6 mL) was added ammonium acetate (1.50 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (430 mg, yield 86%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 411 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=[N:20]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1.Cl>N1C=CC=CC=1>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][C:8](=[O:29])[CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccccc1C1CCC(=NO)C(c2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C1CCC(=O)NC(c2ccccc2)C1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
To a 250mL round-bottomed flask equipped with nitrogen inlet were added 8.20 grams (29.4 mmol) 2-phenyl-4-(2-methylphenyl)cyclohexanone oxime and 80 mL pyridine. Once the solid had dissolved, the solution was cooled to 0° C., and 27.9 grams (147 mmol) p-toluenesulfonyl chloride was added. The reaction was allowed to stir for 16 hours while the ice bath melted and the reaction warmed to room temperature. It was then poured into 300 mL 3N HCl, extracted into ethyl acetate, and the organic layer washed with additional hydrochloric acid and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 5.27 grams (64%) of an amorphous solid.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]([NH2:11])=[O:10])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:2]1[C:3]([C:9]([NH2:11])=[O:10])=[C:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[N:1]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1n[nH]c2c1CCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1c2c(nn1Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.1 %

Procedure:
To a stirring solution of 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (2.57 g, 17.0 mmol) in DMF (34 mL) at 25° C. was added K2CO3 (5.87 g, 42.5 mmol) followed by benzyl bromide (4.36 g g, 25.5 mmol). The reaction was stirred at ambient temperature for 16 h at which time the mixture was diluted with EtOAc (75 mL) and filtered. The filtrate was washed with H2O (100 mL) and the aqueous phase was back-extracted with EtOAc (75 mL) and CH2Cl2 (75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (50% EtOAc in hexanes gradient to 95% EtOAc in hexanes) gave 2-benzyl-2,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (739 mg, 3.07 mmol, 18% yield) isolated as a white solid followed by 1-benzyl-1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (3.24 g, 13.4 mmol, 79% yield) isolated as a white solid.