Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3].CC[O-].[Na+].Cl>C(O)C>[I:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:1][C:2]2=[O:3]
Reactant: CCOC(=O)C(=O)Nc1ccc(I)cc1C(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(I)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a suspension of ethyl ((2-(aminocarbonyl)-4-iodophenyl)amino)(oxo)acetate (20.9 g, 57.7 mmol) in ethanol (300 mL) was added dropwise sodium ethylate (20% ethanol solution, 21.6 g, 63.5 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 0.3N hydrochloric acid (600 mL) under ice-cooling, and the precipitated insoluble material was collected by filtration. The filtered cake was washed with water and ethanol to give ethyl 6-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate as a pale-pink powder (17.0 g, 86%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=1>>[CH2:2]([C:10]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:16][CH:15]=2)[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[N:11]=1)[CH2:1][CH2:6][CH3:5]
Reactant: O=c1[nH]cnc2ccccc12
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The quinazolinone prepared as described in Example 11 was alkylated with 4-bromomethyl-2'-t-butoxycarbonyl-biphenyl. The product was purified by flash chromatography over silica gel eluting with 1% EtOAc/methylene chloride. 1H-NMR (300 MHz, CDCl3): 8.32 (m, 1H), 7.76 (m, 2H), 7.46 (m, 2H), 7.38 (m, 1H), 7.32-7.18(m, 5H), 5.46 (bs, 2H), 2.79 (3 line m, 2H), 1.80 (m, 2H), 1.44 (m, 2H), 1.23 (s, 9H), 0.95 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[CH:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCC(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h
Yield: 46.1 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.1 g) in methylene chloride (20 ml) was slowly added under ice cooling a solution of optically active 1,1,1-trifluoro-2-octanol (0.74 g, [α]D20 =+25.2) and triethylamine (0.4 g) in methylene chloride (10 ml). After the solution was left to stand to reach room temperature, it was stirred for 12 hours. The solution was poured in ice water and was extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water, in the order, and dehydrated over anhydrous magnesium sulfate. The solution was distilled under reduced pressure to remove the solvent until a crude product was obtained. The product was subjected to silica-gel column chromatography to obtain 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate (0.73 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][CH2:9][C@H:5]2[O:4][CH2:3]1.O[C@@H]1[C@H]2N(C(OC(C)(C)C)=O)CC[C@H]2OC1>Cl.O1CCOCC1>[O:4]1[C@H:5]2[C@H:6]([NH:7][CH2:8][CH2:9]2)[C@@H:2]([OH:1])[CH2:3]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CC[C@H]2OC[C@H](O)[C@H]21
Agent: CC(C)(C)OC(=O)N1CC[C@H]2OC[C@H](O)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: O[C@H]1CO[C@@H]2CCN[C@H]12
Reaction time: 1 h

Procedure:
Preparation of (3R,3aR,6aR)-(9H-fluoren-9-yl)methyl 3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2b). Alcohol (2f) (558 mg, 2.43 mmol) was dissolved in 4M HCl in dioxane (14.06 mL) and left to stand at ambient temperature for 1 h. The solvent was removed in vacuo and the residue azeotroped from toluene (3×20 mL) to give hydrochloride salt of (3R,3aR,6aR)-hexahydro-2H-furo[3,2-b]pyrrol-3-ol (2 g) used directly in the following step.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:4](=[O:11])[CH:5]([OH:10])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:3].[Mn]([O-])(=O)(=O)=O.[K+].[OH-].[Na+]>CCCCCC>[CH3:8][C:6]([CH3:9])([C:5](=[O:10])[C:4](=[O:11])[C:2]([CH3:12])([CH3:3])[CH3:1])[CH3:7]
Reactant: CC(C)(C)C(=O)C(O)C(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)(C)C(=O)C(=O)C(C)(C)C
Temperature: 25 °C
Yield: 82.2 %

Procedure:
7.8 g (0.045 moles) of 2,2,5,5-tetramethyl-4-hydroxy-3-hexanone were dissolved in 90 ml of hexane and stirred vigorously with 157 ml of 1M aqueous potassium permanganate solution containing 1.8 g (0.045 moles) of sodium hydroxide. This mixture was then refluxed overnight. The mixture was then cooled to room temperature and the hexane layer separated. The aqueous layer was then extracted three times with 50 ml of hexane. The hexane solutions were then combined and washed three times with 50 ml of pure water before drying over anhydrous magnesium sulfate. The mixture was then filtered and the hexane distilled off at atmospheric pressure to yield 6.3 g of 2,2,5,5-tetramethyl-3,4-hexanedione (82% of theoretical).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:13]1[CH2:16][CH2:15][O:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]1=2
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)OCCO2
Temperature: 70 °C
Yield: 22.8 %

Procedure:
According to the procedure described in Example 6A Step 1, a mixture of ethyl 3,4-dihydroxybenzoate (5.465 g, 30 mmol), 1,2-dibromoethane (5.636 g, 30 mmol), and K2CO3 (6.219 g, 45 mmol) in DMF (100 mL) was heated at 70° C. overnight. The residue was purified by silica gel chromatography with 20-50% EtOAc/hexane as eluants to afford ethyl 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as an oil (1.423 g, 23%). 1H NMR (300 MHz, CDCl3) δ 7.58 (d, 1H), 7.56 (dd, 1H), 6.88 (d, 1H), 4.30 (m, 6H), 1.37 (t, 3H); LC-MS (ESI) m/z 209 (M+H)+.
Reaction SMILES: [Cl-].C[Zn+].[Cl:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](Cl)=[O:8].Cl.[CH2:19](Cl)Cl>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7](=[O:8])[CH3:19]
Reactant: ClCCl
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pd]
Agent: C[Zn+]
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2 M solution of methylzinc chloride in tetrahydrofuran (5.00 mL, 10.1 mmol) is treated dropwise with a solution of 2-chloro-4-fluoro-5-nitrobenzoyl chloride (2.00 g, 8.40 mmol) in tetrahydrofuran, treated with tetrakis(triphenylphosphine)palladium(O) (0.400 g, 0.350 mmol), stirred at room temperature for one hour, and poured into 3 N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a dark liquid. Flash column chromatography of the liquid using silica gel and a methylene chloride in hexanes solution (6:4) gives the title product as an off-white solid (mp 66-68° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:21]2[S:25][C:24]([NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[N:23][CH:22]=2)[N:9]=1.CN.[CH2:38]([N:40](CC)CC)C>CN1C(=O)CCC1>[CH3:38][NH:40][C:27](=[O:28])[NH:26][C:24]1[S:25][C:21]([C:10]2[N:9]=[C:8]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]3[CH3:1])[CH:13]=[C:12]([C:14]([S:17]([CH3:20])(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=2)=[CH:22][N:23]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2cnc(NC(=O)Oc3ccccc3)s2)n1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CN1CCCC1=O
Product: CNC(=O)Nc1ncc(-c2nc(N3CCOC[C@@H]3C)cc(C(C)(C)S(C)(=O)=O)n2)s1

Procedure:
A solution of phenyl N-[5-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidin-2-yl]-1,3-thiazol-2-yl]carbamate (200 mg, 0.39 mmol), methyl amine (1.5 mmol) and triethylamine (0.163 mL, 1.16 mmol) in NMP (3 mL) was heated at 70° C. for 2 hours. The mixture was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate to give the desired material.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[C:24]([Br:25])=[CH:23][C:22](I)=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O>[NH2:14][C:15]1[C:24]([Br:25])=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=2)=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(I)cc(Br)c1N
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)cc(Br)c1N
Temperature: 70 °C
Yield: 174 %

Procedure:
N-Bromosuccinimide (13.5 g, 76.0 mmol) was added in portions over 1.5 h to a stirred solution of methyl 2-amino-5-iodobenzoate (20 g, 72 mmol) in CHCl3 (320 mL) at RT. This was stirred overnight and then silica gel chromatography (step gradient elution with hexane containing 10 to 30% DCM) afforded impure methyl 2-amino-3-bromo-5-iodobenzoate (21 g) as a white solid that was used as such. A flask containing a mixture of 3- (trifluoromethyl)phenylboronic acid (3.73 g, 19 6 mmol), methyl 2-amino-3-bromo-5-iodobenzoate (7.0 g, 16 mmol), K2CO3 (6.85 g, 49 6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.4 g, 1 7 mmol), dioxane (140 mL), and water (28 mL) was degassed and flushed with N2 twice and then heated at 70° C. for 3 h. It was cooled to RT, diluted with EtOAc, washed with water (2×), brine, and then dried over Na2SO4. Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0 to 7% MeOH) afforded impure methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (6.2 g, 10.44 mmol, 63.2% yield) as a white solid that was used as such. A mixture of 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (303 mg, 1.00 mmol), methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (250 mg, 0.668 mmol), tetrakistriphenylphosphine palladium(0) (77 mg, 0.067 mmol), K2CO3 (369 mg, 2.67 mmol) in a microwave vial was flushed with nitrogen and DMF (2.7 mL) was added. The vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried over sodium sulfate, and the solvent removed. Silica gel chromatography (step gradient elution with hexane containing 0, to 20% EtOAc) afforded methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (150 mg, 0.532 mmol, 80% yield). MS (ESI) m/z 470.20 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=2.14 Hz), 7.81 (1H, s), 7.73-7.78 (1H, m), 7.49-7.56 (3H, m), 7.37 (2H, d, J=8.55 Hz), 7.05 (2H, d, J=8.55 Hz), 6.15 (2H, br, s.), 3.95 (3H, s), 3.26-3.38 (4H, m), 2.60-2.69 (4H, m), 2.39 (3H, s).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: CC(CO)(CCCCBr)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Under N2 atmosphere and cooling with an ice bath, 3,4-dihydro-2H-pyran (33.86 g, 0.40 mol) was added dropwise to a stirred solution of 206d (88.0 g, 0.32 mol) and p-toluenesulfonic acid hydrate (0.05 g, 0.03 mmol) in CH2Cl2 (700 mL). After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was filtered through aluminum oxide (160 g) and the aluminum oxide was washed with CH2Cl2 (800 mL). The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 207d (80.0 g, 70%) as an oil. 1H NMR (CDCl3): δ 7.40-7.14 (m 10H), 4.53 (t, 1H, J=3.4), 4.49 (t, 1H, J=3.4), 3.82 (d, 1H, J=9.4), 3.81 (t, 1H, J=9.4), 3.76-3.60 (m, 2H), 3.44 (m, 2H), 3.36 (d, 2H, J=9.4), 3.33 (t, 4H, J=7.0), 1.90-1.42 (m, 14H), 1.79 (t, 4H, J=6.8), 1.37 (s, 6H), 1.34-1.10 (m, 6H). 13C NMR (CDCl3=77.0 ppm): δ 145.67, 127.91, 127.91, 126.39, 126.37, 125.7, 98.95, 98.81, 76.11, 76.07, 62.78, 61.77, 61.66, 41.88, 41.78, 37.93, 37.75, 33.50, 33.44, 30.59, 30.44, 25.41, 25.37, 22.77, 22.71, 22.62, 19.65, 19.23, 19.15. HRMS (LSIMS, nba): Calcd for C15H28BrO2 (MH+): 355.1272, found: 355.1272.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1.O.Cl.C[N:16](C=O)C>O1CCOCC1.CCOCC>[ClH:3].[NH2:16][N:7]1[CH:8]=[C:4]([Cl:3])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(Cl)c[nH]1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Cl)cn1N
Reaction time: 0.33 h
Yield: 85 %

Procedure:
A mixture of sodium hydride (60%, 1.51 g, 38 mmol) and methyl 4-chloro-1H-pyrrole-2-carboxylate (Tetrahedron Letters, 1979, 27, 2505–2508; 4.80 g, 30 mmol) in DMF (40 mL) at 0° C. was stirred for 20 min, then was added 2, 4-dinitrophenolamine (Tetrahedron Lett. 1968, 16, 1909–1910 and J. Heterocyclic Chem. 1967, 413, 7.24 g, 36 mmol), and the reaction mixture was stirred at rt overnight. Water (100 mL) was added to the mixture, and the product was extracted with EtOAc (3×120 mL), the EtOAc solution was washed with 10% LiCl solution (2×120 mL), brine (120 mL), dried over MgSO4 and concentrated in vacuo to give the crude product as a brown oil. This crude product was treated with 4 N HCl in dioxane (8 mL) in Et2O (60 mL), the precipitated solid was collected, washed with Et2O and dried to give the title compound (5.40 g, 85%): 1H NMR (DMSO-d6) δ 7.17 (d, 1H, J=2.2 Hz), 6.68 (d, 1H, J=2.2 Hz), 3.74 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#N.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15].N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:14]([C:13]([C:12](=[O:17])[CH3:11])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O

Procedure:
A solution of 4-cyanobenzonitrile (20 g, 0.15 mol), 2,4-pentanedione (17 g, 0.17 mol), piperidine (130 mg, 1.5 mmol) and p-toluene sulfonic acid (260 mg, 1.5 mmol) in toluene (400 ml) is refluxed overnight with a Dean-Stark trap. The solution is concentrated in vacuo and purified over silica gel with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=[C:12]([OH:22])[CH:11]=2)=[N:4]1)[CH3:2].[N:24]1([C:28]([C:30]2[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:28]([C:30]2[N:31]=[CH:32][C:33]([O:22][C:12]3[CH:11]=[C:10]([CH:15]=[C:14]([O:16][C@@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[CH:13]=3)[C:9]([NH:8][C:5]3[CH:6]=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[O:23])=[CH:34][CH:35]=2)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(O[C@@H](C)COC)c2)n1

Procedure:
The preparation of N-(1-ethyl-1H-pyrazol-3-yl)-3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine was described earlier.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]1[O:33][C:32]2[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][C:24]=2[O:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:32]3[O:33][CH2:22][O:23][C:24]=3[CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc2c(c1)OCO2

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (1.0 g-see Preparation 3), 3,4-methylenedioxyphenethyl bromide (0.9 g), anhydrous potassium carbonate (2.0 g) and acetonitrile (20 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (30 ml) and 5% sodium carbonate (20 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.58 g, m.p. 89°-90°.
Reaction SMILES: CN(C)[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]=1.Cl.[O:16]1CCCC1>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:5]2[CH2:4][C:3]([S:7][C:6]=2[CH:8]=1)=[O:16]
Reactant: COc1ccc2cc(N(C)C)sc2c1
Reactant: C1CCOC1
Agent: Cl
Product: COc1ccc2c(c1)SC(=O)C2
Yield: 80 %

Procedure:
To tetrahydrofuran (200 mL) containing 2-dimethylamino-6-methoxybenzo-[b]-thiophene (cf. U.S. Pat. No. 5,420,349) (20.00 g, 96.5 mmol) was added 1N aqueous HCl (200 mL) and the resulting mixture was heated to reflux for 3 h. The mixture was cooled, the layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic layers washed with water (250 mL), dried (MgSO4), filtered and concentrated to give crude product, which was recrystallized from 3A-ethanol, and dried in vacuo at room temperature to afford the title compound (13.89 g, 77.0 mmol, 80%): mp 80°-82° C.; IR (KBr) 1713, 1605, 1485, 1287, 1015, 865, 813 cm-1 ; 1H NMR (DMSO-d6) δ7.22 (d, 1H, J=8.4 Hz), 7.11 (s, 1H), 6.78 (d, 1H, J=8.4 Hz), 4.06 (s, 2H), 3.71 (s, 3H); 13 C NMR (DMSO-d6) δ203.5, 159.0, 136.9, 125.6, 124.6, 112.3, 108.4, 55.3, 46.2. Anal. Calcd. for C9H8O2S: C, 59.98; H, 4.47; S, 17.78. Found: C, 60.19; H, 4.57; S, 18.03.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[NH:17][C:16](=[O:18])[C:15]([CH:19]([NH:22][C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=O)[CH2:20][CH3:21])=[N:14][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>>[CH:25]1([C:23]2[N:14]3[C:15]([C:16](=[O:18])[NH:17][C:12]([C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([CH3:1])=[CH:3][CH:4]=4)=[N:13]3)=[C:19]([CH2:20][CH3:21])[N:22]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(C)c3ccccc23)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(-c3ccc(C)c4ccccc34)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 1, 797 mg (2.04 mmol) crude N-{1-[3-(4-methyl-1-naphthyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclopentanecarboxamide, 469 mg (3.06 mmol) phosphoric trichloride are stirred at reflux for 3 hours, proportionate amounts of the solvents are used.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:17].C(N(CC)CC)C.[OH-].[Na+].C(OCC)C>C1COCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C@@H:12]([OH:16])[C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[CH3:17]
Reactant: Cc1cc(CC(=O)C(=O)O)cc([N+](=O)[O-])c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](O)C(=O)O)cc([N+](=O)[O-])c1N
Temperature: -35 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere a solution of 12.0 g (37.4 mmol) (1R)-B-chlorodiisopinocampheylborane in 40 mL THF was added dropwise within 15 min to a solution of 6.5 g (26.0 mmol) 3-(4-amino-3-methyl-5-nitro-phenyl)-2-oxo-propionic acid and 4.5 mL (32.4 mmol) triethylamine in 100 mL THF cooled to −35° C. and the reaction solution was stirred overnight at RT. Then the reaction solution was carefully combined with 60 mL 1 M NaOH and 150 mL diethyl ether at 5° C. and stirred for 15 min. The organic phase was separated off, extracted three times with 40 mL 1 M NaOH and once with 40 mL water. The combined aqueous phases were acidified with semiconc. HCl while cooling with an ice bath and extracted twice with 120 mL EtOAc in each case. The combined organic phases were dried over Na2SO4 and evaporated down i.vac. The crude product was obtained, which was further reacted without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21](C)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].O[NH:44]S(O)(=O)=O>C1COCC1.CCCCCC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:44])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1
Reactant: O=S(=O)(O)NO
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC1(C)CC(c2ccc(F)cc2)=C(c2ccc(S(N)(=O)=O)cc2)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 43.9 %

Procedure:
Under nitrogen, a solution of 4.55 g (13.2 mmol) of 1-[2-(4-fluoro phenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene (from Step 10 of Example 1) in 50 mL of THF at -78° C. was treated with 6.3 mL (0.27 mmol) of n-butylllithium (2.5 M in hexane) over a period of 5 minutes. The reaction was stirred at ambient temperature for 25 minutes, cooled to -78° C., and treated with 19.8 mL (19.8 mmol) of tributylborane (1.0 M in THF). The resulting dark brown solution was stirred at ambient temperature for 30 minutes and then at reflux for 14 hours prior to the addition of 8.7 g (106 mmol) of sodium acetate, 37 mL of water, and 5.2 g (46 mmol) of hydroxyamine-O-sulfonic acid. The resulting light orange mixture was stirred at ambient temperature for 6 hours and the aqueous phase extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 2.0 g (40%) of 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1yl)benzenesulfonamide as a colorless solid: mp 117°-118° C.; NMR (CDCl3) §1.24 (s, 6H), 2.70 (s, 4H), 4.72 (s, 2H), 6.92 (t, J=9 Hz, 2H), 7.09 (dd, J=9 and 7 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.74 (d, J=9 Hz, 2H). HRMS. Calc'd for C19H20FNO2S: 345.1199. Found: 345.1194. Anal. Calc'd for [C19H20FNO2S+0.27 H2O]: C, 65.14; H, 5.91; N, 4.00; S, 9.11. Found: C, 65.07; H, 5.94; N, 3.86; S, 9.29.