Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=[O:21])[CH:11]([CH3:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:26]([C:25]2[C:24]([F:23])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([CH3:20])[C:10](=[O:21])[CH:9]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1
Reactant: Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2c(F)cccc2F)c(-c2ccccc2Cl)cc1=O
Yield: 24.5 %

Procedure:
In 200 ml of xylene were dissolved 6.3 g (0.020 mole) of 5-(2-chlorophenyl)-2-methyl-1-phenyl-1,3,5-pentanetrione, 20.0 g (0.155 mole) of 2,6-difluoroaniline, 4.6 g (0.024 mole) of para-toluenesulfonic acid and 50.0 g of Molecular Sieves 5A, followed by reflux for 8 hours. Solid matter was filtered off from the reaction mixture and 300 ml of chloroform was added to the filtrate. The mixture obtained was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. After washing the chloroform layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium solfate, the solvent was distilled off and the residue was subjected to column chromatography (eluent: ethyl acetate) to afford crystals. The crystals were recrystallized from a 2:1 mixed solvent of acetone and hexane, thereby yielding 2.0 g of 6-(2-chlorophenyl)-1-(2,6-difluorophenyl)-3-methyl-2-phenyl-4(1H)-pyridinone having a melting point of 213°-215° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:31]1[CH2:32][C@@H:33]([OH:34])[C@H:29]([NH:28][C:26]([C:22]2[C:18]3=[N:19][CH:20]=[CH:21][C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:17]3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:30]1)(=[O:37])[CH3:36]
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C1(C)C=CC(S(O[CH2:17][C@H:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>>[CH3:23][C:20]1([CH3:24])[O:19][C@@H:18]([CH2:17][N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:22][O:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(I)cn2)O1
Temperature: 100 °C

Procedure:
A mixture of 4-iodopyrazole (1.00 g, 5.16 mmol), (R)-(−)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl p-toluenesulfonate (1.624 g, 5.671 mmol), Cs2CO3 (2.52 g, 7.73 mmol) and DMF (8 mL, 100 mmol) was heated to 100° C. for 2 h. The solution was extracted with EtOAc, and washed with water (2×). The organic layer was concentrated in vacuo and purified via column chromatography, eluting with 2-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=309.00 (100) [MH+]. HPLC: tR=1.32 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Li]CCCC.CON(C)[C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]>>[C:22]([C:3]1[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: CON(C)C(=O)C(C)C
Agent: [Li]CCCC
Product: CC(C)C(=O)c1cccnc1NC(=O)C(C)(C)C
Yield: 69.4 %

Procedure:
A solution of N-(pyridin-2-yl)pivalamide (3.20 g, 18.0 mmol), n-BuLi (15.00 mL, 2.1 eq.) and N-methoxy-N-methylisobutyramide (2.60 g, 1.1 eq) were reacted as outlined in Scheme 1 to give 3.10 g (69%) of N-(3-isobutyrylpyridin-2-yl)pivalamide. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 1.35 (s, 9 H) 3.55 (dt, J=13.70, 6.78 Hz, 1 H) 7.08 (dd, J=7.91, 4.69 Hz, 1 H) 8.19 (dd, J=8.20, 2.05 Hz, 1 H) 8.63 (dd, J=4.83, 1.90 Hz, 1 H) 11.51 (br. s., 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:6]([NH:8]C(=O)C(F)(F)F)[CH:7]=1.[NH2:22][C:23]1[N:28]=[C:27]([NH2:29])[C:26]([CH2:30][C:31]2[CH:32]=[C:33]([O:46][CH2:47][CH3:48])[C:34](I)=[C:35]([O:37][S:38]([CH:41]([CH2:43][CH3:44])[CH3:42])(=[O:40])=[O:39])[CH:36]=2)=[CH:25][N:24]=1>>[NH2:8][C:6]1[CH:7]=[C:2]([C:34]2[C:33]([O:46][CH2:47][CH3:48])=[CH:32][C:31]([CH2:30][C:26]3[C:27]([NH2:29])=[N:28][C:23]([NH2:22])=[N:24][CH:25]=3)=[CH:36][C:35]=2[O:37][S:38]([CH:41]([CH2:43][CH3:44])[CH3:42])(=[O:39])=[O:40])[CH:3]=[CH:4][C:5]=1[CH2:15][N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1I
Reactant: O=C(Nc1cc(Br)ccc1CN1CCOCC1)C(F)(F)F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)CC)c1-c1ccc(CN2CCOCC2)c(N)c1
Yield: 57.7 %

Procedure:
Starting from 308 mg (0.84 mmol) N-(5-bromo-2-morpholin-4-ylmethyl-phenyl)-2,2,2-trifluoro-acetamide and 214 mg (0.422 mmol) butane-2-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 139 mg of the title compound are obtained as pale brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][O:15][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1cccs1
Product: Brc1ccc(OCc2cccs2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and thiophen-2-methanol by the method of Example 10 (b).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=O)[CH2:8][C:9]1[CH:24]=[CH:23][C:12]2[O:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17](=[O:18])[C:11]=2[CH:10]=1)([CH3:5])[CH3:4].S(Cl)(Cl)=O>C(Cl)Cl>[O:18]=[C:17]1[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[CH2:14][O:13][C:12]2[CH:23]=[CH:24][C:9]([CH2:8][C:7]3[O:1][CH2:2][C:3]([CH3:5])([CH3:4])[N:6]=3)=[CH:10][C:11]1=2
Reactant: CC(C)(CO)NC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(Cc2ccc3c(c2)C(=O)c2ccccc2CO3)=N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.9 %

Procedure:
A stirred, ice water cooled mixture of 10.25 g (0.0302 mol) of 6,11-dihydro-N-(1-hydroxy-2-methyl-2-propyl)-11-oxodibenz[b,e]oxepin-2-yl acetamide of Example 2, and 100 ml of sieve dried CH2Cl2 was treated dropwise over a few minutes with 3.95 g (0.0332 mol) of thionyl chloride. The solution was then stirred 15 minutes with cooling and overnight (about 16 hours) at ambient temperature. The solution was washed with 10% sodium hydroxide solution, dried (Na2SO4) and concentrated to an oil which was dried by azeotropic distillation of toluene. On standing overnight at 5° C. the oil crystallized. Recrystallization from 12 ml of isopropanol afforded 6.10 g (62.9%) of crystals of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin2-yl)methyl-4,4-dimethyloxazoline, m.p. 101°-103.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10]C)=O)[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[CH:7]([C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])[CH2:6][S:5][C:4]2[S:12][CH:13]=[CH:14][C:3]1=2
Reactant: Nc1ccccc1
Reactant: COC(=O)C1CSc2sccc2C1=O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)C1CSc2sccc2C1=O
Yield: 89.8 %

Procedure:
A mixture of methyl 5,6-dihydro-4-oxo-4H-thieno[2,3-b]-thiopyran-5-carboxylate (5.7 g, 0.025 mole), aniline (3.5 g, 0.0375 mole) and xylene (180 ml) is refluxed for 2.5 hrs. in a Soxhlet apparatus, the thimble of which contains 20 g of Linde type 4A molecular sieve. The mixture is cooled in an ice bath, and the resulting crystalline precipitate (m.p.155°-158° C.) is collected, dried and recrystallized from methylene chloride and isopropyl ether to give 6.5 g (90%) of off-white crystalline material, m.p. 155°-158° C.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[NH:18][C:17]3[NH:16][C:15](=[O:19])[CH2:14][S:13][C:12]=3[C:11](=O)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:37])=O>>[Cl:37][C:11]1[C:12]2[S:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=[C:9]([S:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:10]=1
Reactant: O=C1CSc2c([nH]c(SCc3ccccc3)nc2=O)N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: O=C1CSc2c(Cl)nc(SCc3ccccc3)nc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of the product from step c) (1.5 g), phosphorus oxychloride (10 ml) and N,N-dimethyl aniline (1 ml) was heated under reflux for 2 hours. The mixture was allowed to cool to room temperature and poured carefully into a saturated sodium bicarbonate solution, and stirred for 15 mins. The crude product was extracted into ethyl acetate and purified (SiO2, dichloromethane as eluant) to give the subtitle compound (0.25 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.IC.Cl[CH2:16]Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:12][N:7]1[C:8]([S:11][CH3:16])=[N:9][N:10]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: ClCCl
Reactant: Cn1c(CCCCO)n[nH]c1=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CSc1nnc(CCCCO)n1C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (1 g) was dissolved in ethanol (6 ml), Iodomethane (0.4 ml) was added dropwise and the reaction was refluxed for 1 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed under reduced to give a crude product that was purified by flash chromatography on silica gel (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.73 g).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]1=2)[CH3:2]>[Pd].C(O)(=O)C>[NH:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:11])([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1)[CH2:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#N)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(C)C(=O)C(C)(C)C(=O)N4CC)ccc21
Yield: 13.8 %

Procedure:
10% Palladium on carbon(0.3 g) was added to an acetic acid solution (20 ml) of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile(1.4 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound(0.19 g) as a colorless oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[H-].[Na+].[CH2:17]([O:19][C:20]([C:22]1[C:26]([Cl:27])=[C:25]([Cl:28])[N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]=1[CH2:34]Br)=[O:21])[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([Cl:27])=[C:25]([Cl:28])[N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]=1[CH2:34][N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(Cl)c(Cl)n(CCC(C)C)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Cl)c(Cl)n1CCC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of tert-butoxycarbonylamino-acetic acid ethyl ester (10.4 g, 51.3 mmol) in 90 mL of N,N′-dimethylformamide at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.35 g, 58.7 mmol). The ice bath was then removed, and the reaction mixture was stirred at ambient temperature for 10 min. After the reaction mixture was cooled at 0° C., the crude 4,5-dichloro-2-bromomethyl-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester (18.1 g, 48.9 mmol) in 20 mL of N,N′-dimethylformamide was added. The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 1 hour. Saturated ammonium chloride aqueous solution (200 mL) and ethyl acetate (350 mL) were added to quench the reaction. The organic layer was washed with water and saturated sodium chloride aqueous solution, dried, filtered, and concentrated to afford 24.1 g of the crude 2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-4,5-dichloro-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a black oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH2:4][C@H:3]1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=[O:10].C1([O:31][C:32](=O)[NH:33][C:34]2[S:35][C:36]([C:40](=[O:42])[CH3:41])=[C:37]([CH3:39])[N:38]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:40]([C:36]1[S:35][C:34]([NH:33][C:32]([NH:1][C@@H:2]2[C@@H:3]([C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:12]3)=[O:10])[CH2:4][S:5](=[O:7])(=[O:8])[CH2:6]2)=[O:31])=[N:38][C:37]=1[CH3:39])(=[O:42])[CH3:41]
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(NC(=O)N[C@H]2CS(=O)(=O)C[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Reaction time: 94 h
Yield: 54.2 %

Procedure:
[(3R,4S)-4-Amino-1,1-dioxo-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-methanone (50 mg, 141 μmol) and [5-acetyl-4-methylthiazol-2-yl]-carbamic acid phenyl ester (43 mg, 155 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (22 μL, 155 μmol). The mixture was stirred at room temperature for 94 h , and then concentrated. The residue was purified by flash column chromatography (4% methanol/dichloromethane containing 0.4% aqueous ammonium hydroxide) to provide a white solid (41 mg, 55%). 1H NMR (300 mHz, CD3OD) δ7.16 (m, 2H), 6.95 (m, 2H), 4.74 (m, 1H), 4.32 (m, 1H), 4.1-3.8 (m, 2H), 3.6-3.5 (m, 2H), 3.4-3.2 (m, 2H), 3.2-2.8 (m, 2H), 2.54 (s, 3H), 2.5 (m, 2H), 2.46+2.44 (2s, 3H), 1.75 (m, 3H), 1.43 (m, 1H), 1.23 (m, 1H), ESI MS: (M+H)+=537.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.C([O:59][C:60](=[O:64])[CH2:61][NH:62][CH3:63])C>>[CH3:34][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([N:62]([CH2:61][C:60]([OH:64])=[O:59])[CH3:63])=[O:30])=[CH:25][C:24]=4[CH:31]=3)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33]
Reactant: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)N(C)CC(=O)O)cc2c1

Procedure:
A solution of 5-{1-[4-(3,3-Dimethyl-2-oxo-cyclohexyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (244 mg, 0.527 mmol) (from example 73A), EDC (151 mg, 0.791 mmol), HOBT (75 mg, 0.554 mmol), triethylamine (0.3 ml, 2.1 mmol), and sarcosine ethyl ester hydrochloride (105 mg, 0.685 mmol) were reacted followed by base hydrolysis as in Example 74 to yield (48 mg, 30%) MS (ES) m/e: 532.3 (M−1)
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([OH:13])[C:11]=1[CH3:12])=[O:6])([CH3:3])[CH3:2].[CH2:20]([O:24][C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34])=[O:26])[CH2:21][CH2:22][CH3:23]>C(#N)C.C1N2CCN(CC2)C1>[CH:1]([O:4][C:5]([C:7]1[S:8][C:9]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:10]([O:13][C:33]([NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25]([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])=[O:34])[C:11]=1[CH3:12])=[O:6])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Reactant: CCCCOC(=O)CCCCCN=C=O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCCCOC(=O)CCCCCNC(=O)Oc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1C
Yield: 93.4 %

Procedure:
10.0 g of 2,5-bis-(isopropoxycarbonyl)-3-methyl-4-hydroxythiophene, 20 ml of anhydrous acetonitrile, 15 g of butoxycarbonylpentyl isocyanate (b.p. 149°-151°/ 13 millibar) and 100 mg of triethylene diamine are maintained at 100° C. for 18 hours. The mixture is diluted with 20 ml of acetonitrile. To remove the excess butoxycarbonylpentyl isocyanate, the reaction mixture is shaken three times with 50 ml of ligroin in each case. The acetonitrile phase is evaporated in vacuo. The evaporation residue is dried at 100° C./0.1 mbar. 16.3 g of 2,5-bis-(isopropoxycarbonyl)-3-methyl-4-[5-(butyloxycarbonyl)pentylaminocarbonyloxy]-thiophene are obtained as a viscous material. 1H--NMR 80 MHz CDCL3 δ-values OCH 2H m 5.0-5.5 ppm; OCH2 2H t 4.13 ppm; N--CH2 2H m 3.1-3.5 ppm; hetar-CH3 s 2.39 ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:43])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[N:37]=[C:38]([CH3:41])[O:39][CH:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[N:37]=[C:38]([CH3:41])[O:39][CH:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:43])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1nc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)co1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3coc(C)n3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-(2-methyl-oxazol-4-yl)-phenyl]-propionic acid tert-butyl ester (0.17 g) (Example K29) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.07 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1)([O-])=O.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:12]1([O:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OC2CCCC2)nc1
Temperature: 80 °C

Procedure:
A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 mL) was heated at 80° C. for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy-5-nitropyridine) was hydrogenated in ethanol using palladium(II) hydroxide as catalyst. The product with the molecular weight of 178.24 (C10H14N20) was obtained in this way; MS (ESI): 179 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])C>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH:15][C:31](=[O:30])[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 130 h

Procedure:
112.5 g (0.41 mmol) of O-benzyltyrosine is suspended in 1 liter of dry methanol and combined at room temperature with 58.9 ml (0.42 mol) of triethylamine. After adding 67 ml (0.53 mol) of trifluoroacetic acid ethyl ester, the mixture is stirred at room temperature for 130 hours under exclusion of moisture. The mixture is separated from unreacted starting material and volatile components are removed by shaking with ethyl acetate/aqueous hydrochloric acid. The ethyl acetate phase is decolorized with activated carbon. Evaporation of the solvents yields 120.7 g (80% of theory) of colorless crystals. Melting point: 149°-150° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[C:34]2([CH3:41])[CH3:40]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH:28][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:37]=2[C:36](=[O:38])[N:35]([CH3:39])[C:34]3([CH3:40])[CH3:41])=[N:3][C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[N:5][CH:6]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CN1C(=O)c2c(N)cccc2C1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4(C)C)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate and 7-Amino-2,3,3-trimethyl-2,3-dihydro-1H-isoindol-1-one (Compound 148A). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.71 (br s, 1H), 8.94 (br s, 1H), 8.35 (s, 1H), 7.43 (dd, J=6.2, 1.9 Hz, 1H), 7.06-7.30 (m, 4H), 6.80 (br s, 2H), 3.80-3.95 (m, 4H), 3.13 (s, 3H), 3.01 (d, J=21.5 Hz, 2H), 1.27 (s, 6H), 1.14 (t, J=7.1 Hz, 6H). MS (ES+): m/z 578.16 [MH+] HPLC: tR=3.27 min (ZQ3, polar—5 min).