Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[C:7]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])[CH:8]=1.S(=O)(=O)(O)O.[CH3:34]O>>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:1][CH3:34])=[CH:8][C:7]=2[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:11])=[N:21]1
Reactant: CO
Reactant: Cc1ccsc1C(=O)Nc1cc(CO)ccc1/C=C/c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Product: COCc1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2sccc2C)c1
Yield: 61 %

Procedure:
To Compound 108 (50.0 mg, 0.13 mmol), methanol (1.00 mL) and sulfuric acid (0.07 mL, 1.30 mmol) were added and the mixture was reacted in a microwave reaction vessel at 100° C. for 5 minutes to obtain Compound 121 (31.6 mg, 61%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[CH3:10][C:11]([NH2:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].[C:19](Cl)(=[O:23])/[CH:20]=[CH:21]/[CH3:22]>>[C:19]([N:18]([C:11]([CH3:17])([CH3:10])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:23])/[CH:20]=[CH:21]/[CH3:22]
Reactant: C/C=C/C(=O)Cl
Reactant: CC(C)(C)CC(C)(C)N
Reactant: CCOC(=O)CCCBr
Product: C/C=C/C(=O)N(CCCC(=O)O)C(C)(C)CC(C)(C)C

Procedure:
Analogously to Example 1, ethyl N-crotonoyl-4-[(1,1,3,3-tetramethylbutyl)amino]butyrate is obtained as a viscous oil by reacting the reaction product of ethyl 4-bromobutyrate and 1,1,3,3-tetramethylbutylamine with crotonic acid chloride, the saponification of which yields N-crotonoyl-4-[(1,1,3,3-tetramethylbutyl)amino]butyric acid (M.P. 92° to 93°).
Reaction SMILES: [N:1]([C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])/[C:7](=[O:16])[NH:8]2)=[N+]=[N-].O.O.[Sn](Cl)Cl>CCO>[NH2:1][C:4]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]2[C:5]=1/[C:6](=[CH:17]/[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])/[C:7](=[O:16])[NH:8]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N=[N+]=[N-])c21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N)c21
Temperature: 25 °C

Procedure:
To a suspension of (Z)-4-azido-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (160 mg, 0.51 mmol) (from Example 43 above) in EtOH (10 mL), was added, at r.t., tin dichloride dihydrate. The heterogeneous mixture was heated at reflux for 6 h then cooled to r.t. The orange solid was collected by suction filtration, washed with ether and dried in a vacuum oven overnight to yield (Z)-4-amino-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 45 mg, 31%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].CC#N.[C:13]1([C@@H:19]([CH3:22])[CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1COCC1.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:21][CH2:20][C@@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:22])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[C@@H](CN)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: C[C@@H](CNc1nc(Cl)nc(Cl)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of cyanuric chloride (677 mg, 3.67 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (6.1 mL) at 0° C. was added a solution of (2R)-2-phenyl-1-propanamine (0.52 mL, 3.7 mmol, 1.0 equiv) in THF (1.8 mL). The reaction mixture was treated with 1 N NaOH to maintain a pH of 9-10 and stirred for 10 min at 0° C. The resulting suspension was used in the next step without workup or purification. MS (ES+): m/e 282.9 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([OH:60])=[O:59])[CH:53]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[CH2:67](Cl)Cl.C[Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([O:60][CH3:67])=[O:59])[CH:53]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(C(=O)O)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(C(=O)OC)c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(m-carboxybenzyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (7 mg) in methylene chloride:methanol (2:1,0.75 mL) at 0° C. was added a methylene chloride solution of trimethylsilyldiazomethane (10% by weight) until a yellow colored persisted. The mixture was then warmed to room temperature, concentrated in vacuo, and purified by flash chromatography on silica gel (acetone:hexane (1:2)) to give the title compound (5.5 mg).
Reaction SMILES: [Mg].[CH:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])([O:13][CH3:14])=[O:12].O.[CH2:27](OCC)C>>[O:24]=[C:23]([CH2:27][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]([O:13][CH3:14])=[O:12]
Reactant: BrCCc1ccccc1
Reactant: CCOCC
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Agent: [Mg]
Solvent: O
Product: COC(=O)CCCCCCCCC(=O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (turnings, 17.1 g) in ethyl ether (300 ml), a solution of β-phenethyl bromide (140 g, 0.7 mol) in ethyl ether was added dropwise under mild reflux with vigorous stirring under nitrogen, and stirring was continued for 1 h under reflux. After cooling, the mixture (Grignard reagent) was added dropwise to a solution of 9-carbomethoxynonanoyl chloride (150.1 g, 0.64 mol) in ethyl ether (500 ml) at -50°~-30° C. The mixture was allowed to warm to room temperature, stirred for 2 h at the same temperature and poured into H2O (500 ml). The organic layer was separated, washed with H2O, dried over anhydrous MgSO4 and evaporated in vacuo. The residue (203 g) was chromatographed on silica gel (Wako Gel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with n-hexane/ethyl acetate (4:1) as eluent to afford the title compound as a colorless oil; yield: 99.7 g.
Reaction SMILES: [NH2:1][S:2]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18](=[O:26])[O:19]CC[Si](C)(C)C)=[CH:12][C:11]=1[O:27]CC1C=CC=CC=1)[CH2:6][C:7](O)=[O:8])(=[O:4])=[O:3].CC(C)([O-])C.[K+]>>[OH:27][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:5]1[CH2:6][C:7](=[O:8])[NH:1][S:2]1(=[O:4])=[O:3])[O:16][CH2:17][C:18]([OH:19])=[O:26]
Reactant: C[Si](C)(C)CCOC(=O)COc1ccc(N(CC(=O)O)S(N)(=O)=O)c(OCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)COc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from N-(aminosulfonyl)-N-(2-(benzyloxy)-4-{2-oxo-2-[2-(trimethylsilyl)ethoxy]ethoxy}phenyl)glycine analogous to Example 295, steps F and G with the modification of using two equivalents of potassium t-butoxide in step F: mp=185-188° C.; 1H NMR (DMSO-d6)δ 9.87 (br s, 1H), 7.22 (d, J=8.6 Hz, 1H), 6.43 (d, J=2.8 Hz, 1H), 6.38 (dd, J=8.8, 2.8 Hz, 1H), 4.62 (s, 2H), 4.32 (s, 2H); (M−1)−=301.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.CC(C)=O.[CH3:11][NH:12][CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:13])[C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: CNC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)N(C)C

Procedure:
A solution of 9 ml (0.05 mmol) of diketene-acetone adduct in 20 ml of toluene was treated with gaseous dimethylamine at room temperature until the reaction was complete. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→10%) yielding 7.0 g of the title compound.
Reaction SMILES: [C:1]([CH2:4][O:5][N:6]=[C:7]([C:11]1[N:15]=[C:14]([NH2:16])[S:13][N:12]=1)[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(=O)([O-])O.[K+].Cl>CN(C)C(=O)C.O.C(OCC)(=O)C>[CH3:17][S:18]([O:9][C:8](=[O:10])[C:7](=[N:6][O:5][CH2:4][C:1]([OH:3])=[O:2])[C:11]1[N:15]=[C:14]([NH2:16])[S:13][N:12]=1)(=[O:20])=[O:19]
Reactant: Nc1nc(C(=NOCC(=O)O)C(=O)O)ns1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OC(=O)C(=NOCC(=O)O)c1nsc(N)n1
Yield: 47.2 %

Procedure:
To a solution of 2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (45.0 g) in N,N-dimethylacetamide (432 ml) was added methanesulfonyl chloride (29.8 g) under stirring and cooling in an ice bath. The mixture was stirred for 25 minutes at 4° to 6° C. and finely powdered potassium hydrogen carbonate (48.4 g) was added thereto. The reaction mixture was stirred for 2.5 hours at 4° to 6° C. and then poured into a cold mixture of ethyl acetate (1.2 l), 1N hydrochloric acid (484 ml) and water (500 ml) below 10° C. under stirring. The organic layer was separated out and the aqueous phase was extracted with ethyl acetate (300 ml). The combined extracts were washed with cold water (800 ml) and a saturated aqueous solution of sodium chloride (800 ml), dried over magnesium sulfate and evaporated. The residue was triturated in methylene chloride (200 ml) to give 2 -carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic methanesulfonic anhydride (syn isomer) (28.0 g), mp. 143° to 146° C. (dec.).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:17]=[C:16]([CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH2:32][CH2:33]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]1([CH2:32][CH2:33][N:23]2[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=3)[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCc1ccccc1
Reactant: c1ccc(-c2cc(CCC3CCNCC3)c3ccccc3n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CCN2CCC(CCc3cc(-c4ccccc4)nc4ccccc34)CC2)cc1

Procedure:
The operation is as in Example 21, starting from 9.3 g of the monohydrochloride of 2-phenyl-4-[2-(4-piperidyl)-ethyl]-quinoline, prepared as indicated in Example 16, 7.3 g of 2-phenyl-ethyl bromide and 18.1 g of potassium carbonate, in suspension in 130 ml of dimethylformamide. 8.3 g are obtained of 4-{2-[1-(2-phenyl-ethyl)-4-piperidyl]-ethyl}-2-phenyl-quinoline melting at 80° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=[O:24])[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C)C=O.ClCCl>[NH2:22][S:19]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:21])=[O:20]
Reactant: ClCc1ccccc1
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
Bumetanide (1.15 g, 3.15 mmol) was dissolved in dimethylformamide (DMF, 10 mL) and benzyl chloride (400 uL, 2.8 mmol) was added followed by triethylamine (480 uL). The reaction was heated to 80° C. for 12 hours, at which time TLC and LC/MS indicated the reaction was complete. The reaction was cooled to room temperature, brought up in dichloromethane and washed with water, saturated ammonium chloride and concentrated to a thick slurry. To the slurry was added water (25 mL). The resultant solids were filtered and dried in a vacuum oven at 50° C. for 12 hours to yield 1.0 g (80%) of benzyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C=C/c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.85 g, 3.02 mmol) in ACN (20 mL), ethyl acrylate (0.605 g, 6.05 mmol), tri-o-tolylphosphine (0.368 g, 1.209 mmol), and TEA (1.204 ml, 9.07 mmol) were added. The reaction mixture was purged with nitrogen and then Pd2(dba)3 CHCl3 adduct (0.313 g, 0.302 mmol) was added. The reaction was heated at 90° C. overnight. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate (15 mL), washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give of (E)-ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)acrylate as a yellow liquid (0.78 g, 76%). 1HNMR: 400 MHz, DMSO-d6: δ 1.25-1.26 (m, 3H), 1.58-1.62 (m, 2H), 1.76-1.77 (m, 1H), 1.97-2.07 (m, 2H), 2.39-2.42 (m, 1H), 3.73-3.79 (m, 1H), 3.88-3.91 (m, 1H), 4.21 (q, J=7.20 Hz, 2H), 5.87-5.88 (m, 1H), 6.64 (d, J=15.60 Hz, 1H), 7.76-7.77 (m, 2H), 7.81-7.87 (m, 1H), 8.12 (s, 1H), 8.18 (s, 1H). LCMS: RT 1.01 min; LCMS (ES-API), m/z 217 (M-THP).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:26][C:25]=4[Cl:38])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.O1CCOCC1>[Pt]=O.CO>[C:1]1([S:7]([NH:10][C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:26][C:25]=4[Cl:38])[C:20]([CH3:22])=[N:21][C:16]3=[CH:15][CH:14]=2)=[O:12])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(/C=C/c2ccccc2)cc1Cl
Agent: O=[Pt]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)nc2n1Cc1ccc(CCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 42.7 %

Procedure:
(E)-5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethenyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (42 mg) was suspended in a mixed solvent of chloroform (4 ml), 1,4-dioxane (2 ml) and methanol (2 ml), and platinum oxide (2 mg) was added. The mixture was stirred at room temperature for 6.5 hr under a hydrogen atmosphere at 1 atm. The reaction mixture was filtrated and the solvent was evaporated. The resultant mixture was purified by silica gel column chromatography (chloroform/methanol=20/1) and crystallized from ethyl acetate/hexane to give 5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (18 mg) as a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19].O>ClCCl>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(C(C)C)cc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a solution of 4-isopropylaniline (1.0 eq) in dichloromethane at 0° C., triethylamine (2.2 eq) was added and stirred for 15 min. Then, acetic anhydride (1.0 eq) in dichloromethane was added at 0° C., after addition the reaction was continued at room temperature for 5 hrs. Water was added and the organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired N-(4-isopropylphenyl)acetamide. (Yield=95%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.CCCCCC.C(OCC)(=O)C>COCCOCCOC>[F:19][C:16]([F:17])([F:18])[C:12]1[CH:11]=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Solvent: COCCOCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(C(=O)c4cccc(C(F)(F)F)c4)cc3)c2cc1OC
Temperature: 160 °C
Yield: 27.7 %

Procedure:
Under argon, 3-trifluoromethylphenyl 4-hydroxyphenyl ketone (432 mg) obtained in Example 139 and 4-chloro-6,7-dimethoxyquinoline (363 mg) were dissolved in diethylene glycol dimethyl ether (10 ml), and the solution was then refluxed at 160° C. for 11 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 204 mg of the title compound (yield: 28%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:36][C@H:35]1[C:37]1[CH:38]=[CH:39][C:40]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:41]([NH:43][CH:44]=[O:45])[CH:42]=1>C1COCC1>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])[CH:21]=1)[CH2:36][C@@H:35]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:41]([NH:43][CH:44]=[O:45])[CH:42]=1)[OH:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNc1cc([C@@H]2CO2)ccc1OCc1ccccc1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCNCc2ccccc2)c1)C1CCCC1
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CN(CCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)Cc2ccccc2)ccc1OCc1ccccc1
Yield: 27.1 %

Procedure:
N-Benzyl-6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexan-1-amine (40 mg) was dissolved in dry THF (0.25 ml) and {5-[(2R)-2-oxiranyl]-2-[(phenylmethyl)oxy]phenyl}formamide (23 mg) (Organic Process Research & Development 1998, 2, 96-99), added. The reaction mixture was heated in a microwave oven for 3 h at 150°. The solvent was removed and the residue purified on a silica SPE bond elut cartridge, eluting with EtOAc-cyclohexane mixtures to give the title compound, (17 mg) LCMS RT=3.1 min
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[CH2:14]([Li])CCC.IC>C1COCC1>[CH3:14][O:1][C:2]12[CH2:3][CH2:4][C:5]([C:10]([O:12][CH3:13])=[O:11])([CH2:8][CH2:9]1)[CH2:6][CH2:7]2
Reactant: COC(=O)C12CCC(O)(CC1)CC2
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C12CCC(OC)(CC1)CC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of methyl 4-hydroxybicyclo[2.2.2]octane-1-carboxylate (8.9 g, 48 mmol) in anhydrous THF (150 mL) at −78° C. was added n-butyl lithium (23 mL, 57.5 mmol, 2.5 M solution in hexane) over 30 min, followed by the slow addition of iodomethane (14 g, 98 mmol). The mixture was stirred at 60° C. for 3 h and quenched by addition of saturated aqueous ammonium chloride solution (50 mL). The resulting solution was concentrated and the residue was extracted with ethyl acetate (150 mL×2). The organic layers were combined and washed with brine, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the title product (6.5 g, 67%). 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (s, 3H), 3.18 (s, 3H), 1.95-1.89 (m, 6H), 1.70-1.65 (m. 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][NH:6][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: NCCc1ccccc1F
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccccc1F)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 250-mL, round-bottomed flask containing a solution of 2-fluorophenethylamine (4.7 mL, 35.9 mmol) and diisopropylethylamine (6.3 mL, 35.9 mmol) in dichloromethane (35 mL) was cooled to 0° C. and treated dropwise with 4-(trifluoromethyl)benzoyl chloride (5.4 mL, 35.9 mmol) over 5 min. The ice-bath was removed after 2 h and the reaction mixture was stirred overnight. The precipitate formed was collected by filtration. The filtrate was diluted with dichloromethane (100 mL) and transferred to a separatory funnel, extracted with water (35 mL), brine (25 mL), and 1N HCl (25 mL). The dichloromethane layer was separated and formation of more precipitate was observed which was collected by filtration. The solids collected were combined and dried under vacuum to yield N-(2-fluorophenethyl)-4-(trifluoromethyl)benzamide as an off-white solid. MS (ESI pos. ion) m/z: 312 (M+H).