Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:9])[CH2:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(Cc1cccc(O)c1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(CC(=O)c2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3'-dihydroxydeoxybenzoin (0.05 mol), ethyl bromoacetate (0.05 mol) ad K2CO3 (0.05 mol) in 50 mL of DMF is stirred at room temperature overnight. The reaction mixture is poured into water and extracted with EtOAc. The organic solution is dried and evaporated to dryness. The crude products are separtated by flash chromatography to give the ethyl 2-(3-(2-(3-hydroxyphenyl)-2-oxoethyl)phenoxy)acetate and the ethyl 2-(3-(2-(3-hydroxyphenyl)-1-oxoethyl)phenoxy)acetate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[CH3:16][S-:17].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:16][S:17][C:2]1[N:3]=[C:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc(-c2cccnc2)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a solution of 4-chloro-5-nitro-2-(pyridin-3-yl)thiazole (500 mg, 2.07 mmol) in 1,4-dioxane (2 mL) was added in one portion solid sodium thiomethoxide (145 mg, 2.07 mmol). The orange-red mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (ethyl acetate/hexanes) to give 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (358 mg, 68%): 1H NMR (300 MHz, CDCl3) δ 9.21 (d, J=5.4 Hz, 1H), 8.79 (dd, J=4.8, 1.8 Hz, 1H), 8.24 (dt, J=7.8, 2.1 Hz, 1H), 7.46 (ddd, J=8.1, 4.8, 0.9 Hz, 1H), 2.81 (s, 3H); EIMS m/z 253.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:33]([F:36])([F:35])[F:34])=[CH:8][C:9]=2[CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=[N:3]1.CN1C=C2C(C(COCC3(C4C=CC=CC=4)CCN(C(OC(C)(C)C)=O)CC3)=CC(C(F)(F)F)=C2)=N1>>[C:27]1([C:14]2([CH2:13][O:12][CH2:11][C:9]3[CH:8]=[C:7]([C:33]([F:34])([F:36])[F:35])[CH:6]=[C:5]4[C:10]=3[NH:2][N:3]=[CH:4]4)[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccccc2)CC1

Procedure:
tert-Butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-Butyl 4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. To a solution of tert-butyl 4-phenyl-4-(((5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (350 mg, 0.715 mmol) in dimethylformamide (4 mL) at 0° C. was added sodium hydride (60% in mineral oil, 57.2 mg, 1.43 mmol). After 5 min, the reaction was treated with iodomethane (0.089 mL, 1.43 mmol). After 30 min, the reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The organics were washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→75% EtOAc/Hex) gave two fractions. The faster eluting fraction was concentrated to give tert-butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (187 mg, 52%). The second fraction was concentrated to give tert-butyl 4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (76.5 mg, 21%). tert-Butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.93 (s, 1H), 7.30 (s, 1H), 7.22 (m, 4H), 7.17 (m, 1H), 4.66 (s, 2H), 3.91 (s, 3H), 3.67 (m, 2H), 3.45 (s, 2H), 3.00 (m, 2H), 2.13 (m, 2H), 1.77 (m, 2H), 1.41 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.0, 142.6, 139.4, 133.9, 128.5, 127.1, 126.5, 124.8, 124.7 (q, J=272 Hz), 124.5, 122.5 (q, J=33 Hz), 121.1, 119.7 (q, J=3.8 Hz), 79.4, 79.2, 70.7, 41.5, 40.0 (br), 38.2, 32.2, 28.5. tert-Butyl 4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate: 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.88 (s, 1H), 7.42 (m, 2H), 7.37 (m, 2H), 7.29 (s, 1H), 7.25 (m, 1H), 4.85 (s, 2H), 4.22 (s, 3H), 3.76 (m, 2H), 3.58 (s, 2H), 3.09 (m, 2H), 2.24 (m, 2H), 1.97 (m, 2H), 1.46 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 147.6, 142.9, 129.2, 128.5, 127.3, 126.4, 125.6, 124.9 (q, J=272 Hz), 124.1 (q, J=33 Hz), 120.7, 118.7, 117.6 (q, J=4.8 Hz), 79.9, 79.3, 68.7, 41.9, 40.7, 40.0 (br), 32.0, 28.6.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[CH:2][CH3:3].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Cl)[CH:14]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]=[CH:2][CH3:3])[CH:14]=1)=[CH:2][CH3:3]
Reactant: CC=Cc1ccccc1O
Reactant: ClCc1cccc(CCl)c1
Product: CC=Cc1ccccc1OCc1cccc(COc2ccccc2C=CC)c1

Procedure:
α,α'-bis-(2-propenylphenoxy)-meta-xylene is prepared in a process similar to Example I, except that 383 grams (2.86 mole) of propenylphenol is employed along with 250 grams (1.43 moles) of α,α'-dichloro-meta-xylene to give a reaction product extracted with methylene chloride, washed with potassium hydroxide and dried over magnesium sulfate, then vacuum distilled at 80° C. to yield 407 grams of a viscous liquid (80% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][Cl:22])=[C:7]([CH2:8][CH2:9][CH3:10])[C:2]=1[OH:1])(=[O:14])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: ClCCCC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC#CCCCCl)ccc(C(C)=O)c1O
Yield: 87.2 %

Procedure:
A mixture of 3.10 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.13 g of 1-bromo-6-chloro-2-hexyne and 3.30 g of anhydrous potassium carbonate in 35 ml of anydrous acetone was stirred at reflux for 2.5 hours. The solvent was removed in vacuo, water was added to the residue and the pH was adjusted to 4.0. The product was extracted with ether and the dried (over magnesium sulfate) extract was chromatographed on 250 g of silica gel. Elution with 25% ethyl acetate-hexane gave 4.30 g (88% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-1-chloro-4-hexyne, the titled compound.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:16])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5](=[O:16])[N:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1c([N+](=O)[O-])cccn1-c1ccccc1
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])cc(Br)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
10 ml of a dimethylformamide solution containing 1 g of 3-nitro-1-phenyl-1,2-dihydropyridin-2-one was incorporated with 988 mg of N-bromosuccinimide, followed by stirring at room temperature overnight. Further, it was stirred at 50° C. for 3 hours. The reaction mixture was poured into ice-water, and the resulting precipitates were collected by filtration, to give 1.27 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].[CH:10]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[CH:34](Br)[CH:35]=O)[CH:29]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:28]2=[O:46])=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O1CCCC1.C(#N)C>[CH:10]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[C:34]1[S:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:9])[CH3:1])=[N:8][CH:35]=1)[CH:29]([NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[C:28]2=[O:46])=[O:25])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: CN(C)CCNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)CCNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 3.2 %

Procedure:
A mixture of 1-(2-dimethylaminoethyl)-thiourea (22 g) in methylene chloride (200 cc) is added to a solution of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (88 g) in anhydrous tetrahydrofuran (500 cc). After having been stirred for 24 hours at 25° C., the reaction mixture is poured onto a mixture of ethyl acetate (1.5 liters) and saturated sodium bicarbonate solution (1.5 liters). The organic phase is washed with saturated sodium bicarbonate solution (1 liter), distilled water (1 liter) and saturated sodium chloride solution (1 liter) and is then dried over anhydrous magnesium sulphate. After filtration, and concentration of the filtrate under reduced pressure (20 mm Hg; 2.7 kPa), the residue is purified by chromatography on silica gel (0.063-0.2 mm) [height of the silica layer: 38 cm, column diameter: 10 cm], elution being carried out with methylene chloride (5 liters) and then with a mixture (11 liters) of methylene chloride and methanol (90:10 by volume), and 1 liter fractions being collected. On concentrating fractions 14 to 16 to dryness, a yellow froth (15 g) is obtained, which is dissolved in hot acetonitrile (100 cc). On cooling, 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl ]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (3 g) is obtained in the form of white crystals (instantaneous melting point, by the Kofler method, 163° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].Br[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[C:26]1([C:7]2[S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]([N:10]([C:17]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH:11]3[CH2:12][CH2:13][N:14]([CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH2:15][CH2:16]3)[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: BrCc1cccnc1
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(Cc3cccnc3)CC2)CC1

Procedure:
Alkylation of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester with 3-bromomethylpyridine and subsequent hydrolysis of the derived ester afforded the title compound compound #121
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[C:10]([C:22](=[O:24])[CH3:23])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:22]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:20])([F:21])[F:19])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:25])=[O:5])[CH:9]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cn(CC(=O)OC(C)(C)C)c2ccc(OC(F)(F)F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reaction time: 8 h

Procedure:
To a solution of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid tert-butyl ester (680 mg, 1.90 mmol) in CH2Cl2 (10 mL) was added TFA (1.47 mL, 19.0 mmol), and stirring was continued at RT overnight. The reaction mixture was then diluted with CH2Cl2 and MeOH, and volatiles were evaporated under reduced pressure. The residue was taken up in MeOH and then evaporated again. The crude material was taken up in 1M aqueous NaOH solution (5 mL), and the water layer was washed with CH2Cl2 and subsequently acidified to pH=1 by addition of a 6M HCl solution. The precipitate was filtered and dried at 50° C. in vacuo for 1 h to afford the title compound as a off-white solid: MS: 302.0 [M+H]+; tR (HPLC conditions c): 4.40 min. The material thus obtained was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=2)[CH2:14][NH:15][C:16]2[C:25]3[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.CC(O)(C)C.CS(C)=O.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>O>[N:41]1([C:2]2[CH:7]=[C:6]([C:8]([NH:10][C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=3)[CH2:14][NH:15][C:16]3[C:25]4[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][N:17]=3)=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C1CCNC1
Reactant: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(N5CCCC5)c4)c3)ncnc12
Temperature: 110 °C
Yield: 49 %

Procedure:
To a 10-mL microwave-rated vial with magnetic stir bar at r.t. was added 4-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-benzylamino}-quinazoline-8-carboxylic acid amide (0.05 g, 0.115 mmol, 1 eq.), t-BuOH (2 mL), DMSO (1 mL), and pyrrolidine (0.1 mL, 1.15 mmol, 10 eq.). The vial was capped and heated under microwave conditions (50 W, 3 min. ramp, 110° C., STND, 1 hr. hold time) followed by addition of another aliquot of pyrrolidine (0.1 mL) then microwaved (70 W, 3 min. ramp, 140° C., STND, 1 hr. hold time). Reaction was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined organics were washed with brine, dried (e.g., Na2SO4), filtered and concentrated. The resulting residue was purified by column chromatography (ISCO CombiFlash) using a 0-30% gradient (10% MeOH in EtOAc/EtOAc) afforded 25 mg (49% yield). LCMS (ESI) 468 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C@@H:17]([N:19]1[C:28](=[O:29])[CH2:27][C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]1=[O:30])[CH3:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:18][C@@H:17]([N:19]2[C:28](=[O:29])[CH2:27][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:21][C:20]2=[O:30])[CH3:16])[CH2:13][CH2:14]1
Reactant: C[C@@H](CCl)N1C(=O)CC2(CCCC2)CC1=O
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Product: C[C@@H](CN1CCN(c2cc(F)ccc2F)CC1)N1C(=O)CC2(CCCC2)CC1=O
Temperature: 160 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
A mixture of 1-(2,5-difluorophenyl)piperazine (20 mg, 0.10 mmol) and (S)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.082 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (10.8 mg, 0.026 mmol, 32%): ESI-MS m/z 406 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14](=[O:15])[CH2:13][C:12](C)(C)[CH2:11][C:10]1=[O:18].[C:19](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:19][O:18][C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[O:15])[C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2ccc(C)cc2C)C(=O)CCC1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 10.00 g (0.0409 mol) of 2-(2',4'-dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione, 21.42 g (0.155 mol) of anhydrous potassium carbonate, 17.59 g (0.124 mol) iodomethane, and 500 ml of anhydrous acetone was refluxed overnight. The reaction mixture was then cooled to room temperature, filtered, and the acetone removed. The residual solid was taken up in 250 ml of CH2Cl2, washed with water, 0.25 N NaOH, 1 N HCl, and water again. The solution was dried (MgSO4) and the solvent removed. The resulting solid was recrystallized from isopropyl ether to give 7.60 g (72% yield) of a white crystalline solid, m.p. 122°-23° C. The compound prepared by the above synthesis has the following structure: ##STR27##
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([CH:21]1[CH2:22][CH:17]([CH2:16][CH2:15][N:14]([CH3:13])[CH3:23])[CH2:18][CH2:19][NH:20]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCC1CCNCC1
Product: CCCCCCC/C=C/C(=O)C1CC(CCN(C)C)CCN1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-(2-dimethylaminoethyl)piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([OH:30])=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[CH3:32].CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[NH:1]([C:8]([C:10]1[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:14][CH:13]=2)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccccc1)n2CC(=O)O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C(=O)Nc2ccccc2)cc2cc(NC(=O)CC(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1.50 g (3.68 mmol) of {2-(anilinecarbonyl)-5-[(3,3-dimethylbutanoyl)amino]-1H-indol-1-yl}acetic acid from Example LIV, 225 mg (1.84 mmol) of 4-dimethylamino-pyridine and 203.5 mg (4.42 mmol) of ethanol are initially charged in dichloromethane. The mixture is cooled to 0° C., and 776 mg (4.05 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl are added. The mixture is stirred at RT for 4 hours. For work-up, the mixture is diluted and extracted with water and dichloromethane. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 2:1–1:1).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:13]1[CH2:23][CH2:22][C@@H:21]([OH:24])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14]1.CCN(CC)CC.O>C(Cl)Cl.CCOC(C)=O>[F:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[CH2:23][CH2:22][C:21](=[O:24])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14]1
Reactant: O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2cccc(F)c2F)Cc2cccnc21
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
In an oven-dried 100 mL round-bottomed flask was OXALYL CHLORIDE (0.131 mL, 1.497 mmol) in CH2Cl2 (4 mL) to give a colorless solution at −55° C. under nitrogen. DMSO (0.212 mL, 2.99 mmol) was added dropwise over 10 min. After the solution was stirred for an additional 30 min, (6R,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (206 mg, 0.748 mmol) (racemic, azeotroped with dry benzene) dissolved in 2 ml CH2Cl2 (plus 2 ml rinse) was added via canuula over 5 min. The reaction mixture was stirred at −50-−55° C. for an additional 40 min (the solution became milky). Et3N (0.521 mL, 3.74 mmol) was added via syringe at −50° C. and the reaction mixture was stirred for 30 min. Water and EtOAc were added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were dried with Na2SO4, and concentrated to a tan oil. TLC (1/1 EtOAc/hexane) showed two spots: the major more polar (comparable to cis-alcohol) and a little SM. Purification by FCC up to 60% EtOAc/hexane afforded the desired product as a colorless oil (148 mg, 72%), plus a little recovered sm. MS (ESI)[M+H+]=274.30. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.57 (dd, J=4.66, 1.64 Hz, 1H) 7.39 (d, J=7.81 Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.04 (m, 2H) 6.72 (t, J=6.92 Hz, 1H) 3.50 (dd, J=9.32, 6.30 Hz, 1H) 3.09 (d, J=6.30 Hz, 2H) 2.84-2.99 (m, 1H) 2.68-2.84 (m, 1H) 2.03-2.17 (m, 1H) 1.85-2.02 (m, 1 H); 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 203.43, 154.56, 152.00-149.39 (dd, J=13.4 and 247 Hz), 149.52-146.94 (dd, J=12.5 and 247 Hz), 148.83, 138.77, 134.44, 134.22 (d, J=11.0 Hz), 125.87, 124.16, 122.36, 115.40 (d, J=17.0 Hz), 39.62, 36.83, 35.19, 27.33.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[S:2]1.[CH2:13]([NH2:16])[C:14]#[CH:15]>>[S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:16][CH2:13][C:14]#[CH:15])=[O:12])[S:2]1
Reactant: O=C(O)CCCC[C@H]1CCSS1
Reactant: C#CCN
Product: C#CCNC(=O)CCCC[C@H]1CCSS1

Procedure:
In amide coupling reaction (as shown in Scheme 10), (S)-5-(1,2-dithiolan-3-yl)pentanoic acid (11) and prop-2-yn-1-amine perform coupling reaction to form (S)-5-(1,2-dithiolan-3-yl)-N-(prop-2-ynyl)pentanamide (12).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][N:16]4[C:23]=3[N:24]=2)=[O:9])[N:4]=[C:3]1[C:25](O)=[O:26].[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH:28]1([NH:33][C:25]([C:3]2[N:2]([CH3:1])[CH:6]=[C:5]([NH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[CH:14]=[C:15]5[C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][N:16]5[C:23]=4[N:24]=3)=[O:9])[N:4]=2)=[O:26])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cn1cc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)nc1C(=O)O
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)nc1C(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 9.8 %

Procedure:
To a solution of 1-methyl-4-{[(6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepin-2-yl)carbonyl]amino}-1H-imidazole-2-carboxylic acid (50 mg, 0.14 mmol) in DMF (1.5 mL) was added cyclopentylamine (27 μL, 0.27 mmol), HOBt (18 mg, 0.14 mmol), N,N-diisopropylethylamine (47 μL, 0.27 mmol), and DMAP (3 mg, 0.027 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol). The mixture is stirred at room temperature for 64 h. The mixture is poured over H2O and the resulting solid is collected by filtration and is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/H2O with 0.1% TFA to obtain the title compound (6 mg, 10%). LCMS: 436.20 (M+H+). (System V-med polar)