Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:37])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:36])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:1][S:2]([NH:5][C:19]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[C:28]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[C:9]([CH3:37])([CH3:8])[CH2:18]2)=[O:20])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)Nc2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a suspension of methanesulfonamide (237 mg, 2.5 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (100 mg, 2.48 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (162 mg, 1 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-N-phenyl-benzamide (100 mg, 18%) as a white solid: LC/MS m/e calcd for C26H27N3O4S (M+H)+: 478.59, observed: 478.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:17])([CH:15]=[CH2:16])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH2:15][C:11]([CH3:17])([CH3:10])[CH:12]=[CH2:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)CC=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: C=CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Yield: 93.2 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 3,3-dimethyl-pent-4-enal (1.2 g, 11 mmol) in CH2Cl2 at room temperature for 18 h to give [3,3-dimethyl-pent-4-en-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.1 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>C1(O)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [O-]c1ccccc1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Product: Brc1ccc2nccc(Oc3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A mixture of 6-bromo-4-chloro-quinoline (1.5 g, 6.18 mmol) and sodium phenoxide (2.32 g, 24.74 mmol) in phenol (8.65 g) was heated to 150° C. in a sealed tube and stirred for 15 h. Then, the suspension was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with 1.0N sodium hydroxide (3×50 mL), brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.33 g (71.6% yield) of 6-bromo-4-phenoxy-quinoline as a light brown solid: EI-HRMS m/e calcd for C15H10BrNO (M+) 298.9946, found 298.9946.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.C([O-])([O-])=O.[Cs+].[Cs+].[SH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C=O)C>[Cl:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]2[S:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:3]=12
Reactant: O=Cc1c(Cl)cncc1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)cncc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,5-Dichloroisonicotinaldehyde (20.39 g, 115.8 mmol) obtained from Aldrich was dissolved in 250 mL DMF. To this solution was added Cs2CO3 (12.9 g, 121.59 mmol) and then methyl 2-mercaptoacetate (56.6 g, 173.7 mmol). The mixture was stirred at room temperature for 3 hours. After removing 200 mL DMF under a reduced pressure, the remaining residue was mixed with 100 mL water. After filtration, the filter cake was washed thoroughly with water and air dried. An off-white solid was obtained as the pure product (23.15 g, y=88%). LCMS (API-ES) m/z (%): 228.2 (100%, M++H); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.96 (s, 3H) 8.12 (s, 1H) 8.64 (s, 1H) 9.36 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:16]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]O)[CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.Cl>O1CCCC1.CO.[OH-].[Na+].C(OCC)C>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][CH3:23])[C:16]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)[CH:25]=1
Reactant: CCCc1cccc(C)c1-c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1cccc(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 0 °C
Yield: 59.4 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.21 g, 1.14 mmol), (2′-methyl-6′-propylbiphenyl-3-yl)methanol (0.25 g, 1.04 mmol) and tributylphosphine (0.39 mL, 1.56 mmol) in tetrahydrofuran (6 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.39 g, 1.56 mmol) with stirring at 0° C., and the mixture was stirred at room temperature for 16 hrs. Diethyl ether was added to the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=4/1) to give as a colorless oil. This product was then dissolved in a mixed solution of methanol (4.0 mL) and tetrahydrofuran (6.0 mL), 1N aqueous sodium hydroxide solution (2.28 mL) was added at room temperature with stirring, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1-1/2) to give the title compound (0.24 g, yield 59%) as colorless crystals. MS (APCI−): 387 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.COC1C=CC=CC=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]C(Cl)=O)=[CH:29][CH:28]=1.COC.Cl.N1C=CC=CC=1.C(=O)C1C=CC=CC=1.N1CCCCC1>CO.C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:33][C:30]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(O)cc1
Agent: COC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(C(=Cc1ccccc1)c1ccc(Cl)cc1)c1ccc(O)cc1
Yield: 44.5 %

Procedure:
8 g (0.0324 mole) of 1-(4-hydroxyphenyl)-2-(4-chlorophenyl)ethanone (prepared by Friedel-Craft reaction between methoxybenzene and 4-chlorophenylacetylchloride, followed by demethylation of the methyl ether with pyridine hydrochloride) was treated with 3.44 g (0.0324 mole) of benzaldehyde and 2.58 g (0.304 mole) of piperidine in 15 ml of methanol at 60° C and worked up as under Example IA gave 9.0 g of crude product. 8.5 g of this material on refluxing with 85 ml of glacial acetic acid for 4 hours and was worked up as under Example IB. Trituration with hot methanol and cooling gave 3 g (44.5%) of crystalline material, m.p. 228°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:22])[N:6]2[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:22])[N:6]2[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1cccc2ccccc12
Yield: 463.7 %

Procedure:
Using the procedure described in Example 1, Part E, 4-hydroxy-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indole (796 mg, 2.8 mmol) was treated with 112 mg (2.8 mmol) of 60% NaH/mineral oil and then 0.27 mL (0.27 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane to give 450 mg (45% yield) of [[2-methyl-1-[(1-naphthalenyl)methyl]-1H-indol-4-yl]oxy]acetic acid methyl ester, 167-171° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[P:8](=[O:22])([S:15][CH2:16][S:17][C:18]([CH3:21])([CH3:20])[CH3:19])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].CO>C(Cl)Cl>[P:8](=[O:22])([S:15][CH2:16][S:17]([C:18]([CH3:20])([CH3:19])[CH3:21])=[O:7])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]
Reactant: O
Reactant: CCOP(=O)(OCC)SCSC(C)(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: CCOP(=O)(OCC)SCS(=O)C(C)(C)C
Temperature: 0 °C

Procedure:
To a suspension of sodium periodate (11.8 grams, 0.055 mole, 10% excess) in 115 ml. of water, cooled to 0° to 5°C., is added O,O-diethyl S-(tert-butylthio)methyl phosphorothioate (13.6 grams, 0.050 mole) and 5.0 ml. of methanol. The reaction mixture, in an ice bath contained in an insulated bucket, is stirred overnight, during which time the ice melts and the mixture attains room temperature. Fifty ml. of methylene chloride is stirred into the mixture and the solids are filtered and washed with an additional 50 ml. of methylene chloride. The filtrate is separated and the aqueous phase extracted with two 50-ml. portions of methylene chloride. The organic solutions are combined, washed with 25-ml. portions of saturated NaCl, 5% KOH, and saturated NaCl (X2), and then dried (MgSO4). Reduced-pressure evaporation of the solvent from the dried solution gives 13.9 grams (96.5%) of clear, colorless oil which slowly crystallizes, melting point 34.5° to 36.0°C. Attempts to effect recrystallization are not successful. TLC shows the presence of only a trace amount of a contaminant.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])[CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:35])([F:34])[F:33])[C:26](=[O:29])[NH:27][N:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]([CH2:30][C@H:31]([OH:36])[C:32]([F:34])([F:35])[F:33])[C:26](=[O:29])[N:27]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=4[Cl:16])[CH:4]=3)[N:28]=2)=[CH:20][CH:19]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1cccc(-c2cc(CBr)ccn2)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2ccnc(-c3cccc(Cl)c3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 16 h

Procedure:
81 mg (0.26 mmol) of the compound from Example 66A were dissolved in 3 ml of acetonitrile and 79 mg (0.26 mmol) of the compound from Example 5A and 125 mg (0.38 mmol) of cesium carbonate were added. The mixture was stirred at 65° C. for 2 h and at RT for a further 16 h. The solid was then filtered off and rinsed with a little acetonitrile. The filtrate was concentrated under reduced pressure and directly purified chromatographically [Method 19]. This gave 79 mg (56% of theory) of the target compound.
Reaction SMILES: B.CSC.[CH:5]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:18](=[O:22])[CH2:19][C:20]#[N:21])[S:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N.CO.C(Cl)Cl>>[NH2:21][CH2:20][CH2:19][CH:18]([C:15]1[S:16][CH:17]=[C:13]([O:12][CH2:11][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:14]=1)[OH:22]
Reactant: N#CCC(=O)c1cc(OCC2CCCCC2)cs1
Agent: B
Agent: N
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: NCCC(O)c1cc(OCC2CCCCC2)cs1

Procedure:
Borane-dimethylsulfide reduction of 3-(4-(cyclohexylmethoxy)thiophen-2-yl)-3-oxopropanenitrile following the method used in Example 2 gave after flash chromatography purification (2%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 18 as a colorless oil. Yield (0.037 g, 43%); 1H NMR (400 MHz, CD3OD) δ 6.62 (dm J=1 Hz, 1H), 6.22 (d, J=1.4 Hz, 1H), 4.85 (m, 1H), 3.71 (d, J=6.3 Hz, 2H), 2.71-2.78 (m, 2H), 1.64-1.97 (m, 8H), 1.15-1.37 (m, 3H), 1.05-1.15 (m, 2H); RP-HPLC tR=9.63 min; ESI-MS m/z 223.1 [C13H18OS2.+H]+ or [M−H2O—CH2NH2+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)=[CH:14][CH:13]=1)[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH:3]([O:2][CH3:1])[C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[CH:17][CH:16]=1
Reactant: COC(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccc(CO)cc1)c1cccc(C#N)c1
Yield: 76 %

Procedure:
A solution of 3-[methoxy-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (0.4 g, 0.976 mmol), tetrahydrofuran (10 mL) and a 1M tetrahydrofuran solution of tetrabutylammonium fluoride (1.2 mL, 1.2 mmol) is stirred at room temperature 18 hr. The mixture is diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL) and the combined extracts are concentrated. The residue is purified via silica chromatography eluting with hexanes to 1:1 hexanes:ethyl acetate to give the title compound (188 mg, 76%) as a colorless oil. LCMS M+1 254.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([NH:19][CH2:20][C:21]([OH:23])=O)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:53]2[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=2)[N:32]2[CH2:35][C:34](=[CH:36][S:37]([CH2:40][C:41]3[CH:42]=[C:43]([N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)[CH:44]=[CH:45][CH:46]=3)(=[O:39])=[O:38])[CH2:33]2)=[CH:27][CH:26]=1>ClCCl>[C:15]([O:14][C:12](=[O:13])[NH:19][CH2:20][C:21]([N:50]1[CH2:51][CH2:52][N:47]([C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][S:37]([CH:36]=[C:34]3[CH2:33][N:32]([CH:31]([C:28]4[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][CH:29]=4)[C:53]4[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=4)[CH2:35]3)(=[O:38])=[O:39])[CH:42]=2)[CH2:48][CH2:49]1)=[O:23])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 20 h
Yield: 102.2 %

Procedure:
1.02 g of supported EDCI (5 mM), 44 mg of N-Boc-glycine and then 10 cm3 of dichloromethane are successively added, at a temperature close to 20° C., to 108.5 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 20 hours at a temperature close to 20° C., the reaction mixture is filtered on sintered glass. The resin is rinsed with three times 5 cm3 of dichloromethane. The combined filtrates are washed with 20 cm3 of water, dried over magnesium sulfate, filtered on sintered glass and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 143 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic acid tert-butyl ester are thus obtained in the form of a cream-colored lacquer [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.40 (s, 9H), 2.93 (s, 3H), from 3.05 to 3.20 (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H), 3.84 (d, J=6 Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.79 (t, J=6 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:12]([Br:13])=[CH:11][N:10]2[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=[C:9]2[CH:8]=1)=[O:6].Cl>O.C(O)C>[Br:13][C:12]1[C:7]([C:5]([OH:6])=[O:4])=[CH:8][C:9]2[N:10]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH:11]=1
Reactant: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2nc(-c3ccccc3)cn2cc1Br
Yield: 96.3 %

Procedure:
NaOH (1N, 61 ml) was added to a suspension of 6-bromo-2-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (10.11 g, 31 mmol) in a mixture of water (30 ml) and ethanol (60 ml), and the mixture was heated to reflux (2 h). The mixture was cooled (0° C.) and HCl (conc., ˜10 ml) was slowly added. The dark brown suspension was filtered, washed with a small amount of ethanol, and dried under vacuum. The obtained title compound (9.47 g, 98%) was used in the next step without further purification. MS (m/e)=318.9 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([N:16]([CH3:18])[CH3:17])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][N:16]([CH3:18])[CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)C1(c2cccc(Cl)c2)CCCCC1
Agent: Cl
Product: CN(C)CC1(c2cccc(Cl)c2)CCCCC1
Yield: 20.2 %

Procedure:
The title compound was synthesized from 1-(3-chlorophenyl)-N,N-dimethylcyclohexanecarboxamide (191 mg, 0.72 mmol) using General Procedure E, followed by HCl salt formation. The crude HCl salt was recrystallized from 2:1 CH3CN:EtOAc (4.5 mL) to give pure (1-(3-chlorophenyl)cyclohexyl)-N,N-dimethylmethanamine hydrochloride as an off-white solid (21 mg, 12%). HPLC Rt=8.41 min; 1H NMR (400 mHz, MeOH-d4) 7.51-7.30 (m, 4H), 3.26-3.24 (m, 2H), 2.54 (s, 6H), 2.24-2.20 (m, 2H), 1.72-1.33 (m, 8h); LC-MS 8.16 min, (M+1)− 252 @ 8.27 min.
Reaction SMILES: [CH:1]1([C@H:4]2[C:8](=[O:9])[CH2:7][CH:6]([CH:10]3[CH2:12][CH2:11]3)[N:5]2C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.Cl.CCN(CC)CC.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH:1]1([C@H:4]2[C:8](=[O:9])[CH2:7][CH:6]([CH:10]3[CH2:11][CH2:12]3)[N:5]2[S:36]([C:33]2[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:40])[F:41])=[CH:35][CH:34]=2)(=[O:38])=[O:37])[CH2:2][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1C(C2CC2)CC(=O)[C@@H]1C1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CC(C2CC2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)[C@H]1C1CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
(2S)-tert-Butyl 2,5-dicyclopropyl-3-oxopyrrolidine-1-carboxylate (20) (127 mg, 0.480 mmol) was placed in dioxane (0.5 mL) and treated with 4N HCl in dioxane (2.0 mL). When reaction was done as indicated by TLC monitoring, it was concentrated in vacuo and used without further purification. This material was dissolved in CH2Cl2 (3 mL) and placed under nitrogen. DMAP (12 mg, 0.096 mmol) and Et3N (0.20 mL, 1.44 mmol) were added and the reaction cooled to 0° C. 4-(Trifluoromethyl)benzene-1-sulfonyl chloride (129 mg, 0.528 mmol) was added and the reaction stirred for 16 hr warming from 0° C. to rt. The reaction was concentrated in vacuo and the resulting crude product was purified by column chromatography using EtOAc/hexane gradients to yield (2S)-2,5-dicyclopropyl-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidin-3-one (21) (149 mg, 83% over two steps) as a 58:42 mixture of diastereomers. The product was a clear oil that solidified upon standing. MS (m/z) 374.1 (M+H)+; retention time (210 nM)=8.329 and 8.500 min, method [7].
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([N+:27]([O-])=O)[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:27][C:4]1[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[CH3:24])=[O:9]
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Yield: 82.4 %

Procedure:
To a solution of 2-(4-chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.55 g, 1.3 mmol) in ethanol (25 mL) was added platinum dioxide on carbon (0.50 g, 5% on carbon). The reaction was subject to 35 psi hydrogen gas for 20 minutes. The reaction was then filtered through celite and the filtrate was concentrated to give the title compound (0.42 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:28])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li+].[OH-]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:28])[N:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCOC(=O)COc1cc(C)c2c(-c3cc(OC)cc(OC)c3)nn(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)cc(-c2nn(C)c3nc(OCC(=O)O)cc(C)c23)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 2-((3-(3,5-dimethoxyphenyl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)oxy)acetate (910 mg, 2.36 mmol) in dioxane (10 ml) and water (10 ml) was added LiOH (113 mg, 4.72 mmol) and the reaction mixture stirred at rt for 72 h. Then, water was added and the mixture extracted with CH2Cl2. The aqueous phase was then adjusted to pH ˜2 with aqueous 2M HCl. The resulting precipitate was then filtered off, washed with H2O and dried under vacuum to furnish 620 mg (74%) of the title compound. [1H-NMR (DMSO-d6, 600 MHz): δ 6.70 (br d, 2H), 6.55 (br s, 1H), 6.44 (s, 1H), 4.49 (s, 2H), 3.91 (s, 3H), 3.78 (s, 6H), 2.50 (s, 3H); UPLC-MS RtJ=0.93 min; [M+H]+=358.1]