Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1[nH]cnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Br)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of ethyl 4-bromo-1H-imidazole-5-carboxylate (400 mg, 1.83 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL) was added sodium hydride (100 mg, 4.17 mmol, 1.00 equiv) in portions. The reaction was stirred at room temperature for 20 min then [2-(chloromethoxy)ethyl]trimethylsilane (300 mg, 1.80 mmol, 1.00 equiv) was added. The resulting solution was stirred at room temperature for 5 h and then diluted with 50 mL of ethyl acetate. The mixture was washed with 3×10 mL of brine then the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 330 mg (52%) of ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.69 (s, 1H), 5.67 (s, 2H), 4.43-4.36 (m, 2H), 3.58 (t, J=10.8 Hz, 2H), 1.45-1.40 (m, 3H), 0.94 (t, J=10.8 Hz, 2H), 0.05 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:19]2[CH:20]=[C:21]([CH3:29])[C:22]([O:27][CH3:28])=[C:23]([CH2:25][OH:26])[CH:24]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[N:3]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:19]2[CH:20]=[C:21]([CH3:29])[C:22]([O:27][CH3:28])=[C:23]([CH2:25][OH:26])[CH:24]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:13]=2)[N:3]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CO
Yield: 74.3 %

Procedure:
(5-(3-Amino-1-(3-bromophenyl)-4-fluoro-1H-isoindol-1-yl)-2-methoxy-3-methylphenyl)methanol (338 mg, 0.74 mmol), pyrimidine-5-boronic acid (110 mg, 0.89 mmol), cesium carbonate (726 mg, 2.23 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (60.6 mg, 0.07 mmol) were dissolved in DME:EtOH:water (6:3:1) (5 mL) and irradiated in a microwave oven for 20 min at 150° C. The solvent was evaporated in vacuo and to the residue was added water, 2 M HCl solution to reach pH˜7, and EtOAc. The organic phase was collected, dried and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 250 mg (74%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]-amide (AMR01038, 80 mg, 0.219 mmol) in dry DCM (6 mL) were added triethylamine (0.3 mL, 2.19 mmol) and methanesulphonyl chloride (0.034 mL, 0.438 mmol). The reaction mixture was stirred at room temperature for 24 h, and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-methanesulfonyl-piperidine-4-carboxylic acid [2-(2,4-dichloro-phenoxy)-phenyl]-amide (47.6 mg, 49%) as an oil. Rf: 0.25 (hexane/EtOAc 4:6). 1H NMR (300 MHz, CDCl3) δ 1.88 (2H, m, CH2), 2.37 (1H, m, CH), 2.72 (3H, s, CH3), 2.78 (2H, m, CH2), 3.71 (2H, td, J=12.5, 3.6 Hz, CH2), 6.67 (1H, dd, J=8.1, 1.3 Hz, ArH), 6.89 (1H, d, J=8.8 Hz, ArH), 6.95 (1H, td, J=8.1, 1.6 Hz, ArH), 7.07 (1H, td, J=8.0, 1.3 Hz, ArH), 7.16 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.43 (1H, d, J=2.5 Hz, ArH), 7.72 (1H, br s, NH) and 8.31 (1H, br d, J=8.1 Hz, ArH). Further purification by flash chromatography on silica gel using hexane/EtOAc 4:6 as eluent gave AMR01051 as a white solid, mp 150-151° C. LC/MS (APCI) tr=4.63 min, m/z 443.37 (M++H, 100), 445.39 (55). HPLC tr=2.52 min (100%)
Reaction SMILES: C[C:2]1[CH:7]=[C:6](N)[C:5]([CH3:9])=[CH:4][C:3]=1N.N[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:13]1[C:14]2[CH2:15][C:6]3[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=3)[C:9]=2[CH:16]=[CH:17][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc(N)c(C)cc1N
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
In the following Examples, 9,9-bis(3-methyl-4-aminophenyl)fluorene (OTBAF) was prepared as described in U.S. Pat. No. 4,684,678, Example 2. It was recrystallized from anhydrous dichloroethane prior to use. p-Phenylenediamine (PDA) was obtained in a sublimed, zone-refined form from Aldrich Chemical Company. 2,5-Dimethyl(p-phenylenediamine) (DMPDA) was obtained from Aldrich and recrystallized from absolute ethanol prior to use. 4,4′-(1,4-Phenylenebis(1-methylethylidene))bisbenzamine (EHPT) was obtained from Shell Chemical Company and was recrystallized from anhydrous dichloroethane prior to use. 9,9-Bis((3,5-dimethyl-4-amino)phenyl)fluorene (DM-OTBAF), 9,9-Bis[(3-ethyl-5-methyl-4-amino)phenyl)]fluorene (DE-OTBAF), and 9,9-bis[(2,5-diethyl-4-amino)phenyl]fluorene (DEAF) were prepared analogously, but using a different aniline derivative, as OTBAF, and were recrystallized prior to use. 3,3′-4,4′-Benzophenone tetracarboxylic acid dianhydride (BTDA) was purchased from Aldrich in a sublimed form. 4,4′-Oxydi(phthalic anhydride) (ODPA) was obtained from Occidental Chemical Company and purified via recrystallization from anisole. Pyromellitic dianhydride (PMDA), 2,2′-bis-((3,4-dicarboxyphenyl)-hexafluoropropane dianhydride (6FDA), 3,3′-4,4′-biphenyltetracarboxylic dianhydride (s-BPDA), and DSDA (3,3′-4,4′-diphenyl sulfone tetracarboxylic acid dianhydride) were purchased and used as received from Chriskev Company of Leawood, Kans.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].Cl.CCOCC.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH2:2][OH:3]
Reactant: OCc1ccccc1
Reactant: O=C(O)CO
Agent: Cl
Solvent: CCOCC
Product: O=C(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Into a solution of glycolic acid (35 gm, 46 mmol) in benzyl alcohol (200 mL) was bubbled anhydrous hydrogen chloride for 1 hr at 0° C. The reaction was then stirred for an additional 4 hrs at 0° C. before it was poured into a mixture of ice water and ether. The layers were separated and the aqueous layer was reextracted with ether. The ether layers were sequentially washed with sodium bicarbonate and brine, combined, dried over sodium sulfate and evaporated. Distillation of the residue at 103°-110° C. 0.5 mm afforded 59 gm (77%) of benzyl glycolate as a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[F:11].[C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)#[CH:14]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]1([C:13]#[C:14][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[C:5]([F:11])[CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C#CC1CCCC1
Reactant: COC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC2CCCC2)cc1F
Temperature: 80 °C
Yield: 93.4 %

Procedure:
4-Bromo-2-fluorobenzoic acid methyl ester (1.0 g, 4.0 mmol) was dissolved in triethylamine (5 mL). To the mixture was added copper iodide (38 mg, 5 mol %), followed by PdCl2(PPh3)2 (140 mg, 5 mol %) and ethynylcyclopentane (0.85 mL, 6.3 mmol). The mixture was heated in a sealed pressure tube at 80° C. for 3 hours. After completion of the reaction, the triethylamine was removed under vacuum and the residue was dissolved in EtOAc and filtered through Celite®. The organic layer was washed with water, brine, and dried (Na2SO4), filtered and the mixture concentrated under vacuum. The residue was purified using column chromatography on sililca using EtOAc-hexane (0-100% gradient) as eluent to give the product (0.92 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
Ethyl (RS-1-(Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-(4-fluorophenyl)-1-hydroxy-3-(3,4methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[N:38]1([CH2:44][CH2:45][NH2:46])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCCN3CCOCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-morpholin-4-yl-ethylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, CDCl3) δ 2.33-2.43 (m, 6 H), 3.25-3.31 (m, 6 H), 3.65-3.71 (m, 4H), 3.84-3.89 (m, 4 H), 5.54 (s, 1 H), 6.08-6.10 (m, 1 H), 6.77-6.80 (m, 1 H), 7.09 (d, J=8.0 Hz, 1 H), 7.27-7.33 (m, 2 H), 7.50-7.57 (m, 2 H), 7.92-7.97 (m, 2 H), 8.13-8.17 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:19]2)[CH2:13][C:14](=[O:17])[NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](Cl)=[O:38]>C(#N)C>[CH3:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37]([O:16][NH:15][C:14]([CH2:13][C@@H:12]([N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH:28][C:29]([CH:31]2[CH2:33][CH2:32]2)=[O:30])[CH2:19]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:17])=[O:38]
Reactant: CCOc1cc([C@@H](CC(=O)NO)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CC#N
Product: CCOc1cc([C@@H](CC(=O)NOC(=O)CC(C)(C)C)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 24 h
Yield: 59.3 %

Procedure:
To a solution of (1R)-cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (500 mg, 1.1 mmol) in acetonitrile (5 mL) was added 3,3-dimethyl-butyryl chloride (0.2 mL, 1.4 mmol) at room temperature and kept for 24 hrs. The solution was extracted with ethyl acetate (50 mL) and sodium hydrogen carbonate (50 mL, sat). The organic layer was dried over MgSO4. Filtration and removal of solvent gave (1R)-cyclopropanecarboxylic acid {2-[2-(3,3-dimethyl-butyryloxycarbamoyl)-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide (360 mg, 59% yield): mp, 118-120° C.; 1H NMR (DMSO-d6) δ 0.87-0.89 (m, 4H, 2CH2), 0.98 (s, 9H, 3CH3), 1.3.1 (t, J=7 Hz, 3H, CH3), 1.73-1.80 (m, 1H, CH), 2.27 (s, 2H, CH2), 3.03-3.06 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.97-4.03 (m, 2H, CH2), 4.18 (d, J=18 Hz, 1H, NCHH), 4.59 (d, J=18 Hz, 1H, NCHH), 5.67 (t, J=8 Hz, 1H, NCH), 6.86-6.94 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 749 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=8 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.82 (s, 1H, NH); 13C NMR (DMSO-d6) δ 7.75, 14.70, 15.46, 29.12, 30.53, 34.67, 44.24, 46.62, 51.11, 55.47, 63.80, 111.94, 112.09, 116.78, 117.33, 117.48, 119.25, 131.23, 132.73, 136.98, 142.26, 147.95, 148.56, 166.54, 168.06, 169.34, 171.70; Anal Calcd for C30H37N3O7+0.1 H2O: C, 65.11; H, 6.78; N, 7.59. Found: C, 64.87; H, 6.87; N, 7.48.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:27][CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]([CH:34]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]([CH2:27][CH2:28][O:29][C:30]3[CH:31]=[CH:32][C:33]([CH:34]=[C:35]([C:40]([O:42][CH3:43])=[O:41])[C:36]([O:38][CH3:39])=[O:37])=[CH:44][CH:45]=3)[C:11](=[O:13])[S:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: O=C(c1ccc2[nH]c(=O)sc2c1)c1ccccc1Cl
Reactant: COC(=O)C(=Cc1ccc(OCCCl)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4Cl)ccc32)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
The compound obtained in Step A is dissolved in DMF and 2 equivalents of potassium carbonate are added. After stirring for 20 minutes at 80° C., 1.2 equivalents of dimethyl 2-[4-(2-chloroethoxy)benzylidene]malonate are added and the reaction is heated for 12 hours. The reaction mixture is then hydrolysed in water and filtered, and the resulting precipitate is recrystallised from methanol to yield the title product.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[C:7]=2[OH:26])[N:14]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(OC)cc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-n2cc(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 401 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH3:22][C@H:23]1OS(=O)(=O)[N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]1.[NH4+].[Cl-]>CN(C=O)C.O.CCCCCC>[C:34]([O:33][C:31]([NH:26][CH2:25][CH2:24][C@@H:23]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[C:4]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CCNC(=O)OC(C)(C)C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 121.1 %

Procedure:
To a suspension of hexane washed 60% sodium hydride in mineral oil (91 mg, 2.3 mmol) in DMF (2.5 mL) under nitrogen atmosphere to 0° C. is added a solution of diethyl 1H-indole-2,6-dicarboxylate (619 mg, 2.4 mmol) in DMF (4 mL). The mixture is stirred for 20 min at 0° C. and a solution of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (518 mg, 2.1 mmol) in DMF (2.5 mL) is added. The reaction mixture is stirred for 30 min at 0° C. and is warmed to room temperature and stirred for 72 h. Water and NH4Cl solution are added and the mixture is stirred for 15 min. The aqueous mixture is extracted with EtOAc (50 mL) and the organic layer is washed with water, brine, dried (MgSO4) and concentrated to afford the title crude compound (1.1 g) which is used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[C:7]([Cl:19])=[CH:6][C:5]=1[O:20][CH3:21].Br[C:24]1[C:29]([C:30]#[N:31])=[CH:28][C:27]([C:32]([F:35])([F:34])[F:33])=[N:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:34])([F:35])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])[C:7]([Cl:19])=[CH:6][C:5]=1[O:20][CH3:21]
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1OC
Product: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Yield: 49.4 %

Procedure:
4-Chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (5.5 g) was prepared according to Step 2E.1 from 4-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (9.8 g) and 5-bromo-2-trifluoromethyl-isonicotinonitrile 1-1 (7.6 g). MS [M+H]+: 371.0; tR=2.83 min (method 1)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:21][O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N2CCCC2=O)cc1
Yield: 94 %

Procedure:
A mixture of 1-(4-carboxyphenyl)pyrrolidin-2-one (3.0 g, 14.6 mmol) from example 1 and sulfuric acid (0.2 mL) in 100 mL of methanol was stirred at reflux for 18 h. The solvent was removed under vacuum. The crude material was dissolved in 100 mL of ethyl acetate and the solution was washed with a saturated sodium bicarbonate solution (3×15 mL), dried and evaporated to give 3.0 g (94%) of 1-(4-methoxycarbonylphenyl)pyrrolidin-2-one as a white solid, mp 118-120° C. (chloroform/ether).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][N:16]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[CH3:17]>C(O)C>[CH3:15][N:16]([C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=2)=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CN(C)c1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(N(C)C)cc2)[nH]c1=O
Reaction time: 19 h
Yield: 55.6 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (20 g) and 4-(N,N-dimethylamino)aniline (19 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 19 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-[4-(N,N-dimethylamino)anilino]-6-oxo-5-pyrimidinecarboxylate (15.7 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(ethyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J7) (300 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (500 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+]([O-])=O)[CH:34]=1)([O-:32])=[O:31]>CN(C)C=O>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=3)=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
334 g (1 mol) of 2-(4-hydroxyphenyl)-2-(4-methylphenyl)hexafluoropropane were dissolved in 1.5 dm3 of dimethylformamide, 276 g of potassium carbonate and 170 g (1.01 mol) of m-dinitrobenzene were added, and the mixture was refluxed for 24 hours. The dimethylformamide was subsequently removed by distillation, and the residue was recrystallized from methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:11]=1[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOCC.[Pd]>[NH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(N)c1C(=O)O
Yield: 65.1 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid (2.19 g, 75 mmol) in methanol (530 mL) and palladium/carbon (0.2 g) was hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was filtered through a pad of Celite, and the filtrate was evaporated to give a foamy brown oil, which was stirred in ether (300 mL) overnight. The suspension was filtered to give 2-amino-6-(tert-butoxycarbonylamino-methyl)-benzoic acid as a yellow solid (13.0 g, 65% yield). The product was used in the next step without further purification.