Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[NH:4][C:3]1=[O:12].[CH2:14](I)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[C:2]([CH3:13])([CH3:1])[C:3](=[O:12])[NH:4]2)[CH:15]=[CH2:14]
Reactant: C=CCI
Reactant: CC1(C)C(=O)Nc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2c1C(C)(C)C(=O)N2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.01 g (5.71 mmol) of 2,3-dihydro-3,3-dimethyl-4-hydroxy-1H-indol-2-one, 1.92 g (5.99 mmol) of allyl iodide, and 1.57 g (11.4 mmol) of potassium carbonate were added to 8.73 ml of N,N-dimethylformamide, and the mixture was stirred for one hour over a water bath at 70° C. After the reaction, the solvent was evaporated and chloroform was added to the residue. The residue was then washed with water, 2N aqueous solution of sodium hydroxide, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, chloroform) to obtain 914 mg (yield: 70.2%) of colorless prisms of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccn2)c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2ccccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 389.15 g/mol.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:4](=O)[CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18].S(=O)(=O)(O)O>CO.[Pd]>[CH3:1][C:2]1([CH3:11])[CH2:3][CH:4]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18])[CH2:6][C:7]([CH3:10])([CH3:9])[NH:8]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Reactant: NCCNCCN
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC1(C)CC(NCCNCCN)CC(C)(C)N1

Procedure:
A mixture of 155 g of triacetone amine, 113 g of diethylene triamine, and 2.5 g of conc. sulfuric acid in 2.5 liters of methanol is hydrogenated in the presence of 7 g of 5% palladium on carbon in the manner described in Example 1. In addition to yielding 1,7-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,4,7-triazaheptane, distillation of the hydrogenation mixture yields at 115°-118° C./0.09 mm Hg 1-(2,2,6,6-tetramethyl-4-piperidyl)-1,4,7-triazaheptane as main product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22]C=O)[CH:18]=3)[C:13]([NH:25][C:26]3[NH:27][N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.Cl>[NH2:22][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([NH:25][C:26]3[NH:27][N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)[C:20]2=[O:21])=[CH:15][CH:16]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc(NC=O)ccc23)[nH]n1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc(N)ccc23)[nH]n1
Reaction time: 2 h
Yield: 47.6 %

Procedure:
9 mg of N-[3-(4-tert-Butyl-phenyl)-1-(5-methyl-2H-pyrazol-3-ylamino)-4-oxo-3,4-dihydro-phthalazin-6-yl]-formamide (ZB-1) in a mixture of 0,5 ml methanol and 0,5 ml conc. HCl were stirred at 50 C for 2 hrs. The mixture was evaporated under vacuum and the residue dissolved in dichloromethane. The dichloromethane solution was washed with sodium bicarbonate solution and evaporated to yield 4 mg of the title product. 1H-NMR: (400 MHz, D6-DMSO) 11.8 (1H, br s), 8.81 (1H, s), 8.02 (1H, d), 7.52 (2H, d), 7.40 (2H, d), 7.34 (1H, d), 6.99 (1H, dd), 6.10 (br s, 2H), 2.10 (3H, s), 1.27 (9H, s); MS (ESI+)=389.21 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:25]=[C:24]([N:26]=[C:27]([NH2:34])[N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[O:23][N:22]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)OCC[O:11]2)[CH:5]=1)[CH3:3]>C(O)(=O)C>[NH2:34][C:27]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[N:26][C:24]1[O:23][N:22]=[C:21]([C:2]([C:4]2[CH:5]=[C:6]([C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:11])[CH:7]=[CH:8][CH:9]=2)([CH3:3])[CH3:1])[CH:25]=1
Reactant: CC(C)(c1cccc(C2(c3ccccc3)OCCO2)c1)c1cc(N=C(N)N2CCOCC2)on1
Solvent: CC(=O)O
Product: CC(C)(c1cccc(C(=O)c2ccccc2)c1)c1cc(N=C(N)N2CCOCC2)on1
Reaction time: 40 h
Yield: 104.2 %

Procedure:
The compound (8.8 mg) obtained in Example 131 was dissolved in 90% aqueous acetic acid solution (2 ml), followed by stirring for 40 hours. The reaction solution was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and thereafter concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain the desired compound (8.3 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CC(=O)CC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Yield: 73.5 %

Procedure:
To a solution of 33.0 g (196 mmol) of methyl 2,4-dihydroxybenzoate and 68.0 g (491 mmol) of potassium carbonate mixed in 500 ml of 2-butanone was added 50 ml (235 mmol) of octyl bromide and the whole was refluxed for 18 hours. Water was added to the solution and the whole was extracted with ethyl acetate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 40.4 g of methyl 2-hydroxy-4-octyloxybenzoate (29) as a colorless clear liquid (yield: 73.5%).
Reaction SMILES: [CH:1]([C:12](OCC)=O)([C:7](OCC)=[O:8])[C:2](OCC)=[O:3].[F:17][C:18]1[C:28]([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[CH:34]=[CH:33][C:32]=2[F:44])=[C:27]([F:45])[CH:26]=[CH:25][C:19]=1[O:20][CH2:21][C:22]([OH:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:3][CH2:2][CH:1]([CH2:7][OH:8])[CH2:12][O:23][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:27]([F:45])=[C:28]([NH:29][CH2:30][C:31]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[CH:34]=[CH:33][C:32]=2[F:44])[C:18]=1[F:17]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCC(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a stirred solution of triethyl methanetricarboxylate (700 mg, 1.73 mmol, 1.0 eq) in DMF (40 mL) was added 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (367 mg, 3.45 mmol, 2.0 eq), TEA (699 mg, 6.91 mmol, 4.0 eq) and HATU (985 mg, 2.60 mmol, 1.5 eq). The resulting mixture was stirred at room temperature overnight under N2. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (DCM:MeOH=100:1-20:1) to give the title compound as a colourless oil (475 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:4]=1[CH2:5][C:6]1[C:7]3[CH:8]2[CH2:9][N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1.CO.P([O-])([O-])(O)=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:4]=1[CH2:5][C:6]1[C:7]3[CH:8]2[CH2:9][NH:10][CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1OC)Cc1cccc3c1C2CN(S(=O)(=O)c1ccc(C)cc1)C3
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1OC)Cc1cccc3c1C2CNC3
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of compound 14 (440 mg, 1.01 mmol), dry methanol (10 mL) and disodium hydrogen phosphate (574 mg, 4.04 mmol) was stirred under nitrogen at room temperature. To this mixture was added 6.20 g of 6% Na--Hg in three portions and the reaction was heated at reflux for 2 h. After cooling, water (200 mL) was added and the mixture was extracted with ether (3×200 mL). The ether layers were combined, dried (MgSO4), filtered (Celite), and evaporated to give an oil that solidified under vacuum. After rotary chromatography 142 mg (50%) of compound 15 was obtained as an oil. The oil quickly darkened on exposure to air and was used immediately for the next step. A small portion of the oil was treated with ethereal HCl and the hydrochloride salt of compound 15 was recrystallized from ethanol-ether: mp (HCl salt) 190° C. (dec); 1H NMR (CDCl3, base) δ3.13 (dd, 1H, J=10.8, 12 Hz, H-1a), 3.50 (dd, 1H, J=3.4, 17.4 Hz, H-1b), 3.70 (m, 1H, H-11b), 3.839 (s, 3H, OCH3), 3.842 (s, 3H, OCH3), 4.03 (dd, 1H, J=6, 12 Hz, H-7a), 4.08 (s, 2H, H-3), 4.33 (d, 1H, J=17.4 Hz, H-7b), 6.78 (d, 1H, J=8.24 Hz, ArH), 6.92 (m, 3H, ArH), 7.11 (t, 1H, J=7.5 Hz, ArH), 7.18 (d, 1H, J=7.5 Hz, ArH); MS (CI) m/z 282 (100); HRCIMS Calculated for C18H19NO2 : 282.1494; Found 282.1497.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([CH:17]2[NH:21][CH2:20][CH2:19][S:18]2)[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>O1CCCC1>[C:13]([C:10]1[CH:9]=[C:8]([CH:17]2[N:21]([C:29](=[O:32])[CH:30]=[CH2:31])[CH2:20][CH2:19][S:18]2)[CH:7]=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[C:11]=1[OH:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)c1cc(C2NCCS2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)N1CCSC1c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.5 %

Procedure:
To a suspension of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazolidine hydrochloride (1.65 g) obtained in Reference Example 61 in tetrahydrofuran (20 ml) was added triethylamine (1.52 g), and acryloyl chloride (0.63 g) was added thereto at 0° C. The mixture was stirred at that temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice-water; and the product was extracted with chloroform. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, and brine, then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 98:2) to afford 0.93 g (54%) of the title compound as colorless crystals. mp 147-149° C. NMR (CDCl3) (200 MHz) δ: 1.40 (18H, s), 3.0-3.2 (2H, m), 3.8-4.0 (1H, m), 4.2-4.5 (1H, m), 5.20 (1H, brs), 5.5-5.8 (1H, m), 5.9-6.6 (3H, m), 6.98 (2H, brs)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([NH2:11])[CH3:10].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([NH:11][C:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:30][CH:29]=1)[C:33]([CH3:45])=[C:34]2[CH3:44])=[O:42])[CH3:10]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1cccc(Cl)c1Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cccc(Cl)c3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2,3-dichlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 571 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccc(F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.02 (2H, m), 7.64 (4H, m), 7.59 (2H, m), 7.13 (2H, m), 6.89 (2H, d), 6.78 (2H, d), 4.16 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(Cl)(=[O:12])CC>>[C:5]([OH:12])(=[O:6])[CH2:7][CH3:8].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CCC(=O)Cl
Agent: Oc1ccc(O)cc1
Product: CCC(=O)O

Procedure:
According to the same procedure as described in Preparation 6, hydroquinone and propionyl chloride were reacted and the reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was thoroughly washed with water and the solvent was removed. The residue was distilled under a reduced pressure to give hydroquinone monopropionate. b.p. 140°-142.5° C./3 mmHg, m.p. 68°-74° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)n2C)c1ccccn1
Yield: 64 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and benzyl chloroformate. Yield: 64% of theory, C35H35N7O5 (633.6) Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1) ##EQU131##
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][N:5]=[C:4]2[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[C:3]=12.Br[C:37]1[CH:38]=[C:39]([CH:43]([OH:49])[C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH:40]=[N:41][CH:42]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:37]2[CH:38]=[C:39]([CH:43]([OH:49])[C:44]([N:46]([CH3:47])[CH3:48])=[O:45])[CH:40]=[N:41][CH:42]=2)=[CH:6][N:5]=[C:4]2[NH:17][CH:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[C:3]=12
Reactant: CN(C)C(=O)C(O)c1cncc(Br)c1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)c(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(O)C(=O)N(C)C)c3)c(Cl)c12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 4-Chloro-3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (38 mg, 0.075 mmol), 2-(5-Bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (29 mg, 0.12 mmol; preparation described below), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (3 mg, 0.004 mmol), acetonitrile (1 mL) and saturated aqueous Na2CO3 (75 μL). The vial was purged with nitrogen, sealed, and irradiated in a Personal Chemistry Optimizer at 120° C. for 30 min. Sodium sulfate was added to the reaction mixture and the slurry was filtered over Celite and concentrated. The crude product was dissolved in 1 mL TFA and stirred at 23° C. for 15 min. The solvent was evaporated and the resulting oil was dissolved in 1 mL DMSO and 50 μL ethylenediamine and purified by mass triggered reverse phase HPLC to afford the title compound (9.5 mg, 0.015 mmol, 25% yield). 1H NMR (500 MHz, DMSO-d6) δ 12.24 (s, 1H), 8.58 (m, 2H), 8.20 (s, 1H), 7.83 (t, J=2 Hz, 1H), 7.33 (td, J=8 Hz, J2=1.5 Hz, 1H), 7.27 (dd, J=7 Hz, J2=1.5 Hz, 1H), 7.05 (d, J=8 Hz, 1H), 6.95 (td, J=8 Hz, J2=1 Hz, 1H), 5.81 (d, J=6.5 Hz, 1H), 5.56 (d, J=6.5 Hz, 1H), 3.68 (s, 3H), 2.95 (s, 3H), 2.84 (s, 3H). MS: m/z 437.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:30])=[CH:32][CH:33]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-imidazol-1-yl benzoic acid. MS: 430.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[CH3:31][CH:32]1[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:36]4[C:35](=[O:37])[CH2:34][CH2:33][CH:32]4[CH3:31])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Reactant: CC1CCC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 12.8 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (116 mg) described in Preparation Example 241 and 5-methylpyrrolidin-2-one (40 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (17 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15](=[O:20])C(Cl)(Cl)Cl)[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)n2c1COCC2
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)n2c1COCC2
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 6-(2,2,2-trichloro-acetyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 4a) (1.2 g, 3.52 mmol) in anhydrous tetrahydrofuran (7 ml) was added pyrrolidine (0.376 g, 5.28 mmol). The resulting mixture was stirred at 55° C. for 1.5 h, and then evaporated to dryness. To the residue was added 15 ml water and 30 ml ethyl acetate and the layers were separated. The aqueous layer was extracted once with 15 ml ethyl acetate. The organic layers were combined and evaporated to dryness. The product was purified by flash chromatography to give 0.95 g (92%) of 6-(pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.14 min; m/z=293.22 (M+H+).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:25]=[C:24]([C:23]([F:36])([F:37])[F:22])[CH:29]=[CH:28][CH:27]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(α, α, α-trifluoro-m-tolyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:20]I)[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4].[CH2:22]([NH:24][CH3:25])[CH3:23]>CC#N>[CH3:1][O:2][C:3]([C:5]1([CH2:20][N:24]([CH2:22][CH3:23])[CH3:25])[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4]
Reactant: CCNC
Reactant: COC(=O)C1(CI)CN(c2c(C)cccc2C)C(=O)C1C
Solvent: CC#N
Product: CCN(C)CC1(C(=O)OC)CN(c2c(C)cccc2C)C(=O)C1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of 1-(2,6-dimethylphenyl)-3-iodomethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step d, 100 mg, 0.25 mmol) in CH3CN (3 mL) was added N-ethylmethylamine (215 μL, 2.5 mmol) and stirred at 80° C. for overnight. Volatiles were evaporated under reduced pressure and purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes) to obtain 1-(2,6-dimethyl-phenyl)-3-[(ethylmethylamino)-methyl]-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (10 mg, 12% yield). LC-MS: Rt (retention time): 0.61 min, MS: (ES) m/z 333.3 (M+H+).