Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](OCC)=[O:17].C[O-].[Na+]>C(O)C>[CH:2]1([C:7]2[NH:9][C:16](=[O:17])[C:12]3[CH2:13][CH2:14][CH2:15][C:11]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)C1CCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(C2CCCC2)nc2c1CCC2
Temperature: 25 °C

Procedure:
A 250-mL round bottomed flask was charged with cyclopentanecarboximidamide hydrochloride (5.38 g, 36.2 mmol), ethyl 2-oxocyclopentanecarboxylate (5.14 g, 38.7 mmol), and ethanol (100 mL). To the stirred mixture at rt was added sodium methoxide (3.91 g, 72.4 mmol). The resulting mixture was stirred under reflux for 22 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL). The solution was extracted with ethyl acetate (4×50 mL). The combined extract was washed with saturated sodium chloride (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound which was carried forward into the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[C:6]1[CH2:10][O:9][C:8](=[O:11])[CH:7]=1.[I-:20].[Na+]>C(#N)C>[Cl:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][N:5]([CH2:4][CH2:3][CH2:2][I:20])[C:6]2[CH2:10][O:9][C:8](=[O:11])[CH:7]=2)=[CH:18][CH:17]=1
Reactant: [I-]
Reactant: O=C1C=C(N(CCCCl)Cc2ccc(Cl)nc2)CO1
Agent: [Na+]
Solvent: CC#N
Product: O=C1C=C(N(CCCI)Cc2ccc(Cl)nc2)CO1
Yield: 87.9 %

Procedure:
27.50 g (91.3 mmol) of 4-[(3-chloropropyl)[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one (I-2) and 51.60 g (344.2 mmol) of sodium iodide in 1.2 l of acetonitrile are heated under reflux for 4 hours. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 31.5 g of 4-[[(6-chloropyridin-3-yl)methyl](3-iodopropyl)amino]furan-2(5H)-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:72][C:73]1[CH:81]=[C:80]2[C:76]([CH2:77][CH2:78][N:79]2[C:82](=[O:84])[CH3:83])=[CH:75][CH:74]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:82]([N:79]1[C:80]2[C:76](=[CH:75][CH:74]=[C:73]([NH:72][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]4[CH2:15][CH2:14]4)(=[O:10])=[O:9])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=3)[CH:81]=2)[CH2:77][CH2:78]1)(=[O:84])[CH3:83]
Reactant: CC(=O)N1CCc2ccc(N)cc21
Reactant: O=S(=O)(NCC1CC1)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCc2ccc(Nc3ccc(S(=O)(=O)NCC4CC4)c(C(F)(F)F)c3)cc21
Reaction time: 12 h

Procedure:
A mixture of 4-Bromo-N-cyclopropylmethyl-2-trifluoromethyl-benzenesulfonamide (51 mg), Pd(OAc)2 (3.2 mg), BINAP (14 mg), cesium carbonate (55 mg) and 1-(6-Amino-2,3-dihydro-indol-1-yl)-ethanone (50 mg) in 15 ml toluene was relaxed for 12 hours. The reaction mixture was eluted through a silica bed with Toluene and then with PE:EtOAc (70:30). The toluene fraction was discarded and the solvent of the PE:EtOAc fraction was removed under reduced pressure. The crude product was purified by Combiflash (linear gradient PE-THF). Yield 32 mg, 49%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].B(Cl)(Cl)Cl.CS[C:16]#[N:17].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl>[C:16]([C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[OH:9])#[N:17]
Reactant: CSC#N
Reactant: CCc1ccc(O)cc1
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(O)c(C#N)c1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
A solution of 4-ethylphenol (2.44 g) in dichloromethane (10 ml), was added to a stirred, ice-cooled, solution of 1M boron trichloride in dichloromethane (24 ml) under argon, followed by methylthiocyanate (1.64 ml), and then anhydrous aluminium chloride (2.66 g). The mixture was stirred for 1 hour at 4° C., then heated at reflux (bath temperature 60° C.) for 4 hours and finally stirred for 16 hours at ambient temperature. The mixture was added cautiously to a stirred, ice-cooled, 4M sodium hydroxide solution and the resultant mixture heated at 70° C. for 30 minutes then cooled. The aqueous phase was separated, washed with dichloromethane (2×25 ml), then acidified to pH 2 with 6M hydrochloric acid and extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed with saturated brine (3×50 ml), dried (MgSO4) and the solvent removed in vacuo to give a brown solid. Purification by flash chromatography, eluting with 20% v/v ethyl acetate in hexane, followed by recrystallisation from hexane gave 2-cyano-4-ethylphenol (A) (2.56 g), m.p. 95°-98° C.; NMR: 1.21 (3H, t, J=7 Hz), 2.59 (2H, q, J=7 Hz), 5.70 (1H, b), 6.90 (1H, m), 7.29 (2H, m).
Reaction SMILES: O[C:2]1([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:15]=[CH:14]3)[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[CH:27]([Si:20]([CH:21]([CH3:23])[CH3:22])([CH:24]([CH3:26])[CH3:25])[N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:2]3[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH3:9])[CH2:4][CH:3]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)([CH3:29])[CH3:28]
Reactant: CC(=O)N1CCC(O)(c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CC=C(c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Reaction time: 72 h
Yield: 66.4 %

Procedure:
1-(4-Hydroxy-4-[1-triisopropylsilyl-1H-indol-5-yl]-piperidin-1-yl)ethanone (3.11 g, 7.4 mmol) in dichloromethane (100 ml) was treated with pyridinium p-toluenesulfonate (3.8 g, 15.1 mmol) and stirred for 72 hours. The solution was poured into water and extracted with dichloromethane (100 ml). The extractions were dried (MgSO4), concentrated and the crude product purified by flash chromatography using ethyl acetate as eluant, to give 1-(4-[1-triisopropylsilyl-1H-indol-5-yl]-1,2,3,6-tetrahydropyridin-1-yl)-ethanone (1.95 g, 66%) as a white solid; δH (CDCl3) 0.80 (18H, d, J 8.5 Hz, 6×CH3), 1.30 (3H, m, 3×CH), 1.75 (3H, d, J 6.7 Hz, COCH3), 2.30 (2H, m, tetrahydropyridinyl H), 3.25 (1H, t, J 5.6 Hz, tetrahydropyridinyl H), 3.40 (1H, t, J 5.6 Hz, tetrahydropyridinyl H), 3.75 (1H, m, tetrahydropyridyl H), 3.85 (1H, m, tetrahydropyridyl H), 5.60 (1H, m, CH=CR), 6.20 (1H, d, J 2.2 Hz, ArH), 6.80 (2H, m, ArH), 7.00 (1H, d, J 7.3 Hz, ArH), and 7.20 (1H, m, ArH).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:46]([CH:47]4[CH2:49][CH2:48]4)=[CH:45][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH:25]([O:27][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:50])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:46]([CH:47]4[CH2:48][CH2:49]4)=[CH:45][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH:25]([OH:27])[CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:50])[CH:14]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(C)[Si](OC1CN(S(=O)(=O)NC(=O)c2cc(C3CC3)c(OCC34CC5CC(CC(C5)C3)C4)cc2F)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: O=C(NS(=O)(=O)N1CC(O)C1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-N-((3-((tert-butyldiphenylsilyl)-oxy)azetidin-1-yl)sulfonyl)-5-cyclopropyl-2-fluorobenzamide (0.28 g, 0.39 mmol) in anhydrous dichloromethane (10 mL) was added tetrabutylammonium fluoride solution (1.0 M in tetrahydrofuran, 1.6 mL, 1.56 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 h. The mixture was quenched with aqueous hydrochloride acid solution (1N, 30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography using 10%-100% gradient ethyl acetate (containing 0.2% acetic acid) in hexanes to afford the title compound as an off-white solid (0.07 g, 36%): 1H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.93 (d, J=13.0 Hz, 1H), 5.83 (d, J=6.0 Hz, 1H), 4.45-4.35 (m, 1H), 4.14-4.09 (m, 2H), 3.89-3.84 (m, 2H), 3.65 (s, 2H), 2.09-1.99 (m, 4H), 1.75-1.67 (m, 12H), 0.94-0.88 (m, 2H), 0.69-0.66 (m, 2H); MS (ES+) m/z 479.3 (M+1); MS (ES−) m/z 477.4 (M−1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[F:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:33]5[CH:32]=[C:31]([F:30])[C:36]([F:37])=[C:35]([F:38])[CH:34]=5)=[CH:3][C:4]([C:26]([F:29])([F:27])[F:28])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Reactant: OB(O)c1ccc(F)c(F)c1F
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
4-Bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b) and 4,5,6-trifluorophenylboronic acid (141 mg, 0.8 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 504 (M+1).
Reaction SMILES: [OH-].[K+].[SH2:3].[CH2:4]([O:6][C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:13]Cl)/[CH:10]=[CH:11]/Cl)[CH3:5]>C(O)C.O>[S:3]1[CH:11]=[CH:10][C:9]([CH:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([O:6][CH2:4][CH3:5])=[O:20])=[CH:13]1
Reactant: CCOC(=O)C(C(=O)OCC)=C(/C=C/Cl)CCl
Reactant: S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccsc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Potassium hydroxide (0.14 g, 2.0 mmol) in ethanol (50 ml) was saturated with hydrogen sulphide at 0° for one hour. To this was added 4-trans ethyl-2-ethoxycarbonyl-5-chloro-3-chloromethylpenta-2,4-dienoate (0.62 g, 2.45 mmol), and addition of hydrogen sulphide was continued for one hour at room temperature. The reaction mixture was stirred for a further four hours. Potassium hydroxide (0.20 g, 2.8 mmol) was added and hydrogen sulphide passed for thirty minutes. The reaction mixture was stirred at room temperature for sixteen hours, diluted with water (50 ml) and extracted with ether (3×50 ml). The extracts were washed with saturated brine, N sodium bicarbonate solution, saturated brine, dried (Na2SO4) and evaporated to give the title compound (78% yield) purified by distillation, b.p. 119°-127°/0.5 mm. δ (CDCl3) 1.27 (6H, t, J 7 Hz, CH3), 4.20 (4H, q, J 7 Hz, OCH2), 4.75 (1H, s, CH), 7.20-7.43 (3H, m, thienyl protons), νmax (film) 1730 cm-1, λmax (ethanol) 234 nm. C11H14O4S requires M, 242.0649. Found M+, 242.0609.
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO.O>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:8]2([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[NH:19]1
Reactant: O=C(C(=O)c1ccccn1)c1ccccc1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccccn2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 1 -phenyl-2-(2-pyridinyl)ethanedione (800 mg, 3.79 mmol) and 2-guanidinobenzimidazole (560 mg, 3.15 mmol) in methanol (20 mL) was treated with a solution of sodium hydroxide (40 mg, 1.0 mmol) in 1 mL of water. The title compound was isolated as pale yellow crystals (160 mg, 20% yield). 1H NMR (300 z, d6 -DMSO) δ 12.0 (br. s, NH, 1H) 11.5 (br s, NH, 2 H), 10.0 (br s, NH, I H), 8.6 br s, NH, 1 H), 8A1 (m, 2 H), 7.55 (t, J=6.9 Hz, 2 H), 7.30-7.10 (m, 8 H), 6.98 (dd, J=6.0, 3.1 Hz, 4 H); MS (ESI) m/z 526 [M+H+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.Br[C:26]1[C:31]([C:32]2[CH:36]=[CH:35][O:34][N:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:23])([F:24])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][N:17]([C:26]2[C:31]([C:32]4[CH:36]=[CH:35][O:34][N:33]=4)=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:18]=1)[CH2:9][CH2:8]3
Reactant: Cc1n[nH]cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: Brc1ncccc1-c1ccon1
Product: Cc1nn(-c2ncccc2-c2ccon2)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Yield: 45 %

Procedure:
This compound is essentially prepared as described in Example 36 by using 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] and 3-(2-bromo-pyrid-3-yl)isoxazole as starting material. Residue is purified by normal phase Isco chromatography (ethyl acetate is used as eluent) to yield 45% of the title compound: mass spectrum (m/z): 518 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[CH:19]\[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)/[C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.C1COCC1.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[CH:19]\[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)/[C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1nccs1)/C(=C/C1CCOCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(/C(=C\C2CCOCC2)C(=O)Nc2nccs2)cc1
Reaction time: 4.5 h

Procedure:
A stirred suspension of (E)-2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 81, 1.54 g, 4.0 mmol) in EtOH (54 mL) and THF (31 mL) was treated with H2O (13 mL), saturated aqueous NH4Cl (13 mL), and Fe powder (1.49 g, 26.7 mmol). After 4.5 h at 20° C., the reaction mixture was filtered through Celite, washing with CH2Cl2. The combined filtrates were concentrated and the residue was dissolved in CH2Cl2. The CH2Cl2 solution was washed with H2O and dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc-MeOH, 19:1) gave (E)-2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide: m/z (ES+)=330.1 [M+H]+. A stirred solution of this compound (104 mg, 291 μmol) in anhydrous CH2Cl2 (4 mL) was treated with MeSO2Cl (90 μL, 1165 μmol) and pyridine (94 μL, 1165 μmol). After 16 h, the mixture was diluted with CH2Cl2 (25 mL), before being extracted twice with 2M NaOH. The combined aqueous extracts were washed with Et2O, before being acidified with 12M HCl to pH1 and extracted twice with CH2Cl2. The combined organic extracts were washed with brine and dried (MgSO4). Filtration and solvent evaporation afforded the title compound: RTB=1.26 min; m/z (ES+)=408.0 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccccn3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M38) (208 mg, 0.39 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (140 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]4[C:12](=[O:33])[NH:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][N:23]([C:30]=3[CH:31]=4)[C:24]=2[C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C1COCC1.[Pd]>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]4[C:12](=[O:33])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][N:23]([C:30]=3[CH:31]=4)[C:24]=2[C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cn2c(-c3ccoc3)c(C3CCCCC3)c3ccc(cc32)C(=O)NCCC=CCCN1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Cn2c(-c3ccoc3)c(C3CCCCC3)c3ccc(cc32)C(=O)NCCCCCCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 1 (30 mg, 0.067 mmol) and 10% Pd/C (20 mg) in methanol (10 mL) and THF (10 mL) was shaken in a hydrogenation apparatus under 55 psi pressure at room temperature for 1 h. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated to dryness. Filtration on silica gel afforded 24 mg (80%) of the target product 2: m/z=448 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([OH:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.C[N:36](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([NH2:36])=[O:28])[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylic acid (0.090 g) in N,N-dimethylformamide (9 mL) were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (71 mg) and 1-hydroxybenzotriazole ammonium salt (0.056 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The suspension was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=70:30-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.058 g, yield 65%) as colorless crystals. MS: 486 (MH+). melting point 241-243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.ClCC#N.[CH3:14][CH2:15][O:16]CC>[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]1[C:4]2[C:15](=[O:16])[CH2:14][O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOCC
Reactant: COc1cccc(O)c1
Agent: N#CCCl
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cccc2c1C(=O)CO2
Yield: 13 %

Procedure:
These compounds were prepared from 3-methoxyphenol (1) (6 ml, 55 mmol), ZnCl2 (8.2 g, 60 mmol), and chloroacetonitrile (4.2 g, 66 mmol) in dry ether (100 ml). Purification of the crude product by column chromatography (eluent: CH2Cl2/MeOH: 99/1) gave (2) (1.147 g, 13%), a single compound by HPLC (98% pure, recrystallized from EtOH). 1H-NMR (Acetone-d6, 400 MHz): (7.45 (1 H, d); 6.64 (2 H, m); 4.62 (s, 2 H); 3.95 (s, 3 H) and the more polar compound (3) (1.48 g, 17%). HPLC (84% purity). 1H-NMR (Acetone -d6): δ (400 MHz): values corresponded to previous synthesis of (3).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](O)=[O:19])=[CH:16][C:3]1=2.O1CCCC1.B.CO>O.CCCCCC.CCCCCC.C(OCC)(=O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: B
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2COc2ccc(CCO)cc21
Temperature: 5 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A stirred solution (-17° C.) of 6.71 g (0.025 mol) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid and 18 ml of anhydrous tetrahydrofuran was treated dropwise over 15 minutes with 24 ml of 1.06M borane in tetrahydrofuran solution (approximately 0.025 mol BH3). After total addition, the cooling bath was allowed to equilibrate overnight (about 16 hours) to ambient temperature. The resultant stirred, chilled (5° C.) solution was treated with 5 ml of methanol, diluted with 50 ml of water and concentrated on a rotary evaporator at 40° C. to remove the organic solvents. The residue was diluted with water (70 ml) and CH2Cl2 (70 ml) and was washed with 5% NaHCO3 solution until the aqueous phase had a pH of 8. The organic phase was dried (Na2SO4) and then filtered. The resultant organic phase was concentrated to an oil (5.51 g) which was dried by azeotropic distillation of toluene (70 ml). A portion of the oil was dissolved in 8 ml of anhydrous ethyl acetate, diluted to the cloud point with hexane (7 ml) and was then treated dropwise with ethyl acetate (0.6 ml) until a clear solution was obtained. The solution was subjected to high pressure liquid chromatography with hexane/ethyl acetate (60:40). The product-containing fractions were combined and concentrated to an oil (2.08 g). On standing at 5° C., some crystals formed and were stirred into the oil. On trituration of the mixture with hexane the oil solidified. The material was isolated by vacuum filtration, washed with hexane and dried in vacuo at ambient temperature to afford 1.42 g (22.3%) of a solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol, m.p. 78°-81.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[Mg]Br>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(C)c([Mg]Br)c1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(C2(O)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-Benzyl-4-piperidinone (946 mg, 5 mmol) was added to 5 mL anhydrous THF and cooled to 0° C. under nitrogen. 10 mL of 2,5-dimethylphenylmagnesium bromide (0.5 M solution in THF) was added drop-wise. The reaction was stirred at 0° C. for 10 minutes, then allowed to warm to room temperature and stirred for 1 h. The reaction was concentrated, and brought back up in methanol/H2O/acetic acid (1:1:0.5). The solution was filtered and purified by reverse-phase HPLC (2-99% CH3CN/0.085% TFA) to yield 1-benzyl-4-(2,5-dimethyl-phenyl)-piperidin-4-ol 3a. MS (ESI) m/z (M+H+) 296.2.