Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.[C:56]1([CH2:62]O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Yield: 62.4 %

Procedure:
A mixture of compound 7 (3 g) and N,N-dimethyl-4-pyridinamine (1.22 g) in DCM (100 ml) was stirred till complete dissolution. 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.8 g) was added portionwise and the mixture was stirred at room temperature for 15 minutes. A solution of benzenemethanol (0.54 g) in DCM was added. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent CH2Cl2/CH3OH 97/3 to 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 2.06 g (62%) of phenylmethyl 6,11-dihydro-11-[1-[2-[4-(2-quino-linyl-methoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate (compound 9).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH2:24][CH2:25][C:26]2([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:31][C:30](=[O:32])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH:12]=[C:13]([CH2:22][CH3:23])[C:14]=1[O:15]COCCOC>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:24][CH2:25][C:26]2([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:31][C:30](=[O:32])[CH2:29][C:28](=[O:33])[CH2:27]2)[CH:12]=[C:13]([CH2:22][CH3:23])[C:14]=1[OH:15]
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OCOCCOC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.07 mL, 0.88 mmol) was added to a solution of 6-{2-[3-Chloro-5-ethyl-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione (0.2 g, 0.44 mmol) dissolved in CH2Cl2 (4 mL). The reaction mixture was stirred for 2 hours at room temperature and then partitioned between H2O and EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 30% EtOAc in hexanes) to give the title compound as a solid. (0.12 g, 75%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3H), 1.58-173 (br m, 8H), 1.92 (m, 2H), 2.26 (m, 1H), 2.57 (m, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.76 (s, 2H), 3.43 (s, 2H), 5.47 (s, 1H), 6.81 (s, 1H), 6.95 (s, 1H). MS: C20H24O4Cl (M−H) 363.10.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH:11][CH3:12].ClCCl.O>COCCOC>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:11]([CH3:12])[CH3:10])[N:7]=1
Reactant: CNC
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CN(C)c1nc(Cl)nc(Cl)n1
Temperature: -5 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Cyanuric chloride (11.0 g, 59.6 mmol) was dissolved in ethylene glycol dimethyl ether (100 ml), cooled to -5° C. and gradually added dropwise with 50% aqueous dimethylamine solution (10.8 ml, 120 mmol). This reaction mixture was stirred at the same temperature for 2 hours and then stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residue obtained was added with dichloromethane and water, and then was shaken for mixing. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed to obtain 11.0 g (yield: 95.4%) of 2,4-dichloro-6-dimethylamino-1,3,5-triazine as colorless crystals having melting point of 122.5° C.-123° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].CN(C)C(=N)N(C)C.[C:25]([O:29][C:30](N=[N+]=[N-])=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30]([NH:2][CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NC(CCCC(=O)O)Cc1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of crude 5-amino-6-phenylhexanoic acid hydrochloride (0.235 g, 0.97 mmoles) prepared as described in Example 1 and tetramethylguanidine (0.438 g, 2.90 mmoles) in dimethylformamide (6.60 mls) is treated with t-butoxycarbonylazide (0.276 g, 1.93 mmoles) in dimethylformamide (3.00 mls) and the solution stirred for 48 hours at room temperature. The dimethylformamide is evaporated and the product partitioned between ethyl acetate and 1 M citric acid. Extraction of the organic phase with 3% aqueous ammonia followed by acidification and extraction affords 5-t-butoxycarbonylamino-6-phenylhexanoic acid, which is further purified by preparative t.l.c. using benzene-dioxane-acetic acid (95:25:4 v/v/v) for development. Elution with ethyl acetate affords the pure acid as a white solid (0.180 g, 53% based on 5-phenyl-4-phthalimidopentanoic acid). Crystallisation from ethyl acetate/petrol (60°-80° C.) gives the acid in the form of a white powder, m.p. 94.5°-96.5° C.; τ(CDCl3): -0.67 (1H, s,D2O-exchangeable), 2.82 (5H,s), 5.58 br (1H, D2O-exchangeable) 6.28 br (1H), 7.28 (2H,d, J=6.5Hz), 7.68 (2H multiplet), 8.05-8.90 (10H, complex); νmax (CHCl3): 2600 (very broad) 1710, 1500 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:4][C:3]=1[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(N)ccc1Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc(Br)c(C)c1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
4-Bromo-3-methylaniline (5.00 g, 27 mmol) and triethylamine (4.5 ml, 32 mmol) were stirred in dichloromethane (200 ml) as ethyl chloroformate (3.1 ml, 32 mmol) was added dropwise. The mixture was stirred for 2 h, when water was added. After stirring for a further 15 min, the white precipitate was filtered off, and the filtrate was separated. The organic portion was dried (Na2SO4) and evaporated to give the title compound (2.57 g, 37%) as an orange-brown oil.
Reaction SMILES: [Li].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:13]1[CH2:16][C:15](=[O:17])[CH2:14]1>CCOCC.C1COCC1>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][C:15]2([OH:17])[CH2:16][O:13][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCc1ccccc1
Reactant: O=C1COC1
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(CCCCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Under argon atmosphere at −45° C., to a stirred mixture of Lithium in pellets (0.129 g, 18.7 mmol) suspended in dry Et2O (15 mL), 4-bromo-butylbenzene (1.5 g, 7.03 mmol) in dry Et2O (10 mL), was added dropwise. The reaction was left to stir at 0° C. for 3 h, then the mixture was transferred via a cannula to a solution of 3-oxetanone (0.4 g, 5.55 mmol) in dry THF (10 mL), previously cooled to −78° C. After 3 h at −78° C., the reaction mixture was quenched with a saturated NH4Cl solution, the organic solvents removed under reduced pressure. The crude mixture was then dissolved in CH2Cl2, dried over Na2SO4, concentrated to dryness and subjected to column chromatography using a Teledyne ISCO apparatus, eluting with Cy/TBME (from 100:0 to 70:30) to afford a pure compound (0.4 g, 35%) as colorless oil. 1H NMR (CDCl3): δ 1.41-1.55 (m, 2H), 1.65-1.78 (m, 2H), 1.84-1.94 (m, 2H), 2.62-2.73 (m, 2H), 4.52 (d, J=7.2 Hz, 2H), 4.58 (d, J=7.0 Hz, 2H), 7.21 (dd, J=5.4, 7.2 Hz, 3H), 7.27-7.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CC(N(C)C)=O>[CH3:20][C:21]1([C:24]([NH:1][C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)=[O:25])[CH2:23][CH2:22]1
Reactant: CC1(C(=O)O)CC1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)CC1

Procedure:
A solution of EXAMPLE 89 (20 mg, 0.08 mmol), 1-methylcyclopropanecarboxylic acid (10 mg, 0.096 mmol), HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium) (38 mg, 0.1 mmol) and triethylamine (20 mg, 0.2 mmol) in dimethylacetamide (2.5 mL) was stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in a 1:1 mixture of dimethylsulfoxide/methanol, and separated by HPLC (Waters Sunfire® C-8 analytical column [Milford, Mass.], 0.1% trifluoroacetic acid/water/CH3CN) to provide the title compound. MS (DCI/NH3) m/z 338 (M+H)+; 1H NMR (500 MHz, D2O/dimethylsulfoxide-d6): δ 0.57-0.69 (m, 2H), 1.02-1.10 (m, 2H), 1.38 (s, 3H), 1.57-1.65 (m, 4H), 2.29-2.44 (m, 4H), 3.87 (s, 2H), 6.89 (d, J=7.63 Hz, 1H), 7.23 (t, J=7.93 Hz, 1H), 7.42 (s, 1H), 7.46 (d, J=8.24 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.COC[C@@H](O)C>O>[CH3:17][O:13][CH2:14][C@H:15]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:16]
Reactant: C1CCOC1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC[C@@H](C)Oc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.6 %

Procedure:
To a solution of 2-methylquinolin-8-ol (1.0 g, 6.3 mmol) in tetrahydrofuran (5.2 mL, 6.3 mmol) was added triphenylphosphine (6.9 g, 26 mmol), diethyl azodicarboxylate (1.6 mL, 10 mmol), and (S)-1-methoxypropan-2-ol (0.80 mL, 8.2 mmol) and the resultant mixture allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by reverse phase chromatography on C18 (0-80% acetonitrile/water) afforded the title compound (0.46 g, 28%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][N:6]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10])=[CH:5][N:6]=1
Reactant: CO
Reactant: Cc1ncc(CCC(=O)O)s1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnc(C)s1

Procedure:
A mixture of 31.7 g of the product of Step B, 3.2 ml of concentrated sulfuric acid and 300 ml of methanol was refluxed for 16 hours and was evaporated to dryness under reduced pressure. The residue was taken up in 100 ml of water and concentrated ammonium hydroxide was added thereto to adjust the pH to 12-13. The mixture was extracted with methylene chloride and the extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 35 g of raw methyl 2-methyl-5-thiazole-propanoate. Reaction with hydrochloric acid resulted in the hydrochloride melting at 115° C.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([NH:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][N:12]=1)[CH2:3][CH2:2]2.[NH:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[NH:18][CH:19]=[CH:20]4)=[CH:13][N:12]=1)[CH2:3][CH2:2]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1ccc(NC2CCN3CCCC2C3)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: c1cc2cc(-c3ccc(NC4CCN5CCCC4C5)nc3)ccc2[nH]1
Yield: 43.9 %

Procedure:
A microwave vial containing a stirring bar is loaded with 148 mg (0.5 mmol) of (4SR,5RS)-(1-aza-bicyclo[3.3.1]non-4-yl)-(5-bromo-pyridin-2-yl)-amine, 98 mg (0.61 mmol) of indole-5-boronic acid and 29.7 mg of tetrakis(triphenylphosphine)palladium, capped and after evacuation purged with argon. After addition of 9 ml of toluene, 1 ml of EtOH and 1 ml of 2 M Na2CO3 soln. the mixture is irradiated at 120° C. for 45 min in a microwave reactor (Initiator Exp, Biotage). The reaction mixture is filtered over hyflo and diluted with AcOEt. The aq. phase is extracted with AcOEt, the combined organic phases are washed with water and brine, dried over Na2 SO4 and evaporated. The residue is purified by medium pressure chromatography on silica gel with AcOEt/MeOH/NEt3 50:45:5 affording a foam which after trituration with pentane yields 73 mg of (4SR,5RS)-(1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridin-2-yl]-amine as beige powder. MS (ES+): m/e=333 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36]CC)=[O:35])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:24])=[C:21]([F:41])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[C:21]([F:41])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1F)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(CNc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c4)cc3c2c(=O)[nH]1
Yield: 101.1 %

Procedure:
A solution of diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate (2.3 g, 4.1 mmol) in ethanol (25 ml) and 0.2 N NaOH (100 ml) was stirred under nitrogen at room temperature for 3 hours. The solution was adjusted to pH 7 with 1 N HCl and reduced in volume under vacuum to remove the ethanol. The product was precipitated by acidifying the solution with 1 N HCl to pH 3 with stirring under nitrogen. The suspension was stirred 15 minutes, filtered under nitrogen, washed with water, pressed with a sheet of latex to remove excess water, and dried under high vacuum to give N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quina-zolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamic acid as a white solid (2.1 g). 1H NMR (DMSO-d6,300 MHz) d: 1.82-2.12 (m, 2H, glu CH2), 2.29 (t, J=7 Hz, 2H, glu CH2), 2.43 (s, 3H, C3—CH3), 4.32-4.42 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9—CH2), 6.39 (dd, J=15.2 Hz, 1H, Ar), 6.53 (dd, J=9.2 Hz, 1H, Ar), 7.30 (t, J=6 Hz, 1H, ArNH), 7.47 (dd, J=9.9 Hz, 1H Ar), 7.59(d, J=9 Hz, 1H, Ar), 7.61(dd, J=8.2 Hz, 1H, Ar), 7.73 (t, J=7 Hz, 1H, glu NH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.42 (br s, 2H, CO2H's), 12.53 (s, 1H, N2H). Anal. Calculated for C26H23FN4O6. 3/2 H2O.1/3 NaCl: C, 56.49; H, 4.74; N, 10.14; Cl, 2.12; Na, 1.37. Found: C, 56.48; H, 4.64; N, 10.20; Cl, 2.01; Na, 1.30.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
17.64 g (128 mmol) of 4-hydroxybenzoic acid (Aldrich, purity 99%) and 14.32 g (255 mmol) of potassium hydroxide are dissolved in 30 ml of distilled water and added to 260 ml of ethanol. After addition of 33.0 g (29.7 ml, 0.17 mol) of 1-bromooctane (Aldrich, purity 99%), the solution is heated at the boil for 24 hours with stirring. A further 14.32 g (255 mmol) of potassium hydroxide are then added, and the mixture is refluxed with stirring for a further two hours. After the reaction batch has been cooled, the solvent is substantially removed under reduced pressure, and the residue is taken up in distilled water and strongly acidified using 2 M hydrochloric acid solution. The residue is extracted with chloroform, dried over magnesium sulfate, evaporated and recrystallized from acetone.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:33][C:32]1[C:24]([F:23])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:34])=[CH:26]2)#[N:13]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ccnc4cc(OCCCN5CCCC5)c(C#N)cc34)ccc2[nH]1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (500 mg, 1.58 mmol), 4-fluoro-5-hydroxy-2-methylindole (314 mg, 1.9 mmol) and cesium carbonate (775 mg, 2.38 mmol) in DMF (15 ml) was heated at 95° C. for 2 hours. After removal of the volatiles by evaporation under vacuum, the residue was dissolved in methylene chloride and poured onto a column of silica and eluted with a mixture of methylene chloride/methanol (90/10) followed by methylene chloride/methanol/methanol saturated with ammonia (88/10/2). The fractions containing the expected product were combined and evaporated to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (558 mg, 79%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>O>[Br-:33].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S+:11]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)(C)c1ccc(Br)cc1
Solvent: O
Product: CC(C)(C)c1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Product: [Br-]

Procedure:
The target compound was obtained by following the procedure of Synthesis Example 1 aside from using bis(4-tert-butylphenyl)sulfoxide instead of the diphenyl sulfoxide and 4-tert-butylbromobenzene instead of the chlorobenzene in Synthesis Example 1, and increasing the amount of water for extraction.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:22])[NH:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21].[CH2:23]([C:25]1[CH:30]=[C:29]([CH2:31]Br)[CH:28]=[CH:27][N:26]=1)[CH3:24].O.C(#N)C>CN(C)C=O>[CH3:3][C:4]1([CH3:22])[N:8]([CH2:31][C:29]2[CH:28]=[CH:27][N:26]=[C:25]([CH2:23][CH3:24])[CH:30]=2)[C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[C:5]1=[O:21]
Reactant: CCc1cc(CBr)ccn1
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1cc(CN2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2(C)C)ccn1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
0.009 g of sodium hydride is added to a solution of 0.064 g of 5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione in 1 ml of anhydrous dimethylformamide, under an inert atmosphere of argon, at a temperature in the region of 20° C. Stirring is continued at this temperature for 30 minutes. A solution of 0.062 g of 2-ethyl-4-(bromomethyl)pyridine in 0.5 ml of anhydrous dimethylformamide is added, followed by addition of ice-cold water after reaction for 10 minutes. The reaction mixture is placed on a cartridge 27 mm in diameter packed with 25 g of octadecyl-grafted 40-60 μm silica conditioned successively with the mixture (water/acetonitrile)(5/95)(v/v) and then with the mixture (water/acetonitrile)(95/5)(v/v). The elution is performed with a mixture (water/acetonitrile) (95/5)(v/v) over 20 minutes, followed by a linear gradient of from 5% to 95% acetonitrile over 60 minutes, at a flow rate of 10 ml/minute. The fractions between 750 and 790 ml are concentrated under reduced pressure. 0.06 g of 5,5-dimethyl-1-(2-ethylpyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione is thus obtained, the characteristics of which product are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:10]2)[CH:5]=[N:6][CH:7]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2[N:12]([CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[C:13](=[O:14])[N:9]([CH2:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30]([F:41])([F:40])[F:29])[CH:3]=3)[N:10]=2)=[CH:23][CH:24]=1
Reactant: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1n(Cc2cncc(-c3ccccc3C(F)(F)F)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.15 mmol) of the compound from Example 28A and 43 mg (0.23 mmol) of 2-(trifluoro-methyl)phenylboronic acid were dissolved in 2 ml of dioxane. For 10 min, a stream of argon was passed through this solution, and 8.7 mg (0.008 mmol) of tetrakis(triphenylphosphine)palladium(0) were then added under argon. The mixture was heated to the boil, and 0.15 ml (0.30 mmol) of a 2 N aqueous sodium carbonate solution was added under argon. The mixture was stirred under reflux for 20 h. After cooling to RT, the mixture was diluted with 10 ml of water and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 36 mg (44% of theory) of the target compound.