Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.035 g, 0.12 mmol) was treated with α,α,α-trifluoro-m-tolylisocyanate (0.025 g, 18.0 μL, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 11 (0.038 g, 0.080 mmol, 65%) as a white solid. LCMS m/z (%)=469 (M+H79Br, 91), 471 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.42 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.64-7.73 (m, 2H), 7.45-7.53 (m, 2H), 7.44 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[NH3:27]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([NH2:27])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (40 mL) was chilled in an ice bath and saturated with ammonia gas. The cooling bath was removed and the mixture was stirred at room temperature for 4 hours and the solution was evaporated to dryness. Crystallization from tetrahydrofuran-ethyl alcohol provided 0.4 g of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 194°-196° C.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C@@H:24]([NH2:26])[CH3:25]>>[CH3:11][C:8]1([CH3:12])[CH2:7][O:6][C:5]2([CH2:4][CH2:3][C:2]([CH2:15][CH2:16][NH:26][C@H:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH3:27])[CH3:25])([OH:1])[CH2:14][CH2:13]2)[O:10][CH2:9]1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: Cc1ccccc1[C@H](C)N
Product: Cc1ccccc1[C@H](C)NCCC1(O)CCC2(CC1)OCC(C)(C)CO2
Yield: 37 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-o-tolyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 37% of theory; LC (method 8): tR=1.16 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([CH3:28])[N:22]=1>CS(C)=O>[Cl:20][C:21]1[N:22]=[C:23]([CH3:28])[N:24]=[C:25]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH:26]=1
Reactant: CNS(=O)(=O)Cc1ccc(O)cc1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
Under nitrogen atmosphere add potassium carbonate (26.4 g, 190.8 mmol) to a solution of 1-(4-hydroxyphenyl)-N-methyl-methanesulfonamide (19.2 g, 95.4 mmol), and 4,6-dichloro-2-methylpyrimidine (15.6 g, 95.4 mmol) in DMSO (192.0 mL). Stir the resulting mixture at room temperature for 2 hours. Pour the mixture into 400 mL of ice/water (1:1 v/v) to induce precipitation. Stir the resulting suspension for 30 minutes. Collect the solid; wash with water; and dry under reduced pressure overnight to provide the title compound as a pale brown solid (27.7 g, 89%). MS (m/z): 328 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31].[OH-].[Na+]>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: N
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccccc2)no1

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.48 g, 3.53 mmol) was treated with a solution of 7 M ammonia in methanol (25 mL) at 150° C. for 17 hours. The volatiles were removed under reduced pressure and the resulting oil was diluted with dichloromethane and 1 M hydrochloric acid. A white solid formed and 50% aqueous sodium hydroxide was added to dissolve the solid. The aqueous layer was separated and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. Upon treatment of the oil with diethyl ether, a solid formed. The solid was purified by flash chromatography (silica gel, eluting with a mixture of 95% dichloromethane and 5% of a solution of 80% chloroform, 18% methanol, and 2% NH4OH (CMA)) followed by several recrystallizations from acetonitrile to provide 2-(ethoxymethyl)-1-[(3-phenylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.505 g) as a white powder, mp 215.0-216.0° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[CH3:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Product: Cc1cccc(C=C2CCNCC2)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3-methyl-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (287.4 mg, 1 mmol) in CH2Cl2 (1 mL) TFA (1 mL) is added. The solution is stirred for 2 h at 20° C. The solvent is evaporated, the residue dissolved CH2Cl2 (75 mL) and washed with 1 M aqueous NaOH (2×20 mL). The organic layer is dried (Na2SO4), filtered and concentrated to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][CH:11]([CH3:13])[CH3:12].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cc1
Yield: 19.5 %

Procedure:
4-bromophenol (2.4 g, 13.8 mmol), 1-iodo-2-methylpropane (3.45 mL, 20 mmol), sodium hydroxide (0.8 g, 20 mmol) and DMF (2 mL) were allowed to react to yield the sub-title compound (615 mg, 19%).
Reaction SMILES: [CH3:1][O-].[Na+].[OH:4][CH2:5][CH2:6][C:7]1[C:8](=[O:15])[NH:9][C:10]([CH3:14])=[N:11][C:12]=1[CH3:13].IC>CO>[OH:4][CH2:5][CH2:6][C:7]1[C:8](=[O:15])[N:9]([CH3:1])[C:10]([CH3:14])=[N:11][C:12]=1[CH3:13]
Reactant: Cc1nc(C)c(CCO)c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: Cc1nc(C)n(C)c(=O)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Sodium methylate (1.9 g) was added to a mixture of intermediate 4 (6 g) in methanol (50 ml) while stirring at RT. Stirring was continued for 30 minutes and iodomethane (5 g) was added dropwise and the reaction mixture was stirred and refluxed for 4 hours. The solvent was evaporated, water was added to the residue and this mixture was extracted with CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated, yielding 6.0 g (94%) of 5-(2-hydroxyethyl)-2,3,6-trimethyl-4(3H)-pyrimidinone (intermediate 5).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH2:22][S:23]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[NH:21][N:36]=[C:22]3[S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCN(Cc4ccccc4)C3)cc12

Procedure:
A mixture of 4-(1-benzylpiperidin-3-yloxy)-2-(1-naphthylsulfonylmethyl)phenylamine (1.0 g, 2 mmoles) in THF and 4M HCl (10 mL), under nitrogen, at 3° C. was treated dropwise with a solution of sodium nitrite (0.16 g, 2.4 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.7 g, 1.4 mmoles).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](CCO)=[C:18]([N+:29]([O-:31])=[O:30])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:17][C:18]=1[N+:29]([O-:31])=[O:30])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)c2ccccc2c1CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCc1c([N+](=O)[O-])cc(OCc2ccccc2)c2ccccc12
Reaction time: 8 h

Procedure:
Acetic anhydride (0.35 mL, 3.71 mmol) was added to a solution of 2-[4-benzyloxy-2-nitronaphthalen-1-yl]ethanol ((0.3 g, 0.93 mmol) in dry pyridine (3 mL) at room temperature and stirred overnight. The mixture was concentrated and dissolved in AcOEt (50 mL). The organic layer was washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL), and then the organic layer was dried (Na2SO4) and concentrate. The residue was purified by silica-gel column (AcOEt: Petroleum ether=1: 6) to yield 2-[4-benzyloxy-2-nitronaphthalen-1-yl]ethyl acetate ((0.21 g, 62%) as a yellow solid. mp 82-87° C.; 1H NMR (CDCl3, 500 MHz) δ 8.43 (d, 8.5, 1H), 8.33 (d, 8.5, 1H), 7.33 (dt, 1.0, 7.5, 1H), 7.66 (dt, 1.0, 7.0, 1H), 7.54 (d, 7.5, 2H), 7.45 (t, 7.5, 2H), 7.40 (t, 7.0, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 4.47 (t, 7.0, 2H), 3.55 (t, 7.0, 2H), 2.06 (s, 3H); EIMS m/z 388 (M+Na+); IR (neat) νmax 1738, 1593, 1527, 1514, 1466, 1424, 1365, 1337, 1235, 1104, 1043, 770, 752, 698 cm−1.
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.CN1CCOCC1.Cl>C(OCC)(=O)C>[C:19]1([CH3:28])[CH:24]=[CH:23][C:22]([C@@H:25]([NH:27][C:12](=[O:17])[C@H:13]([CH:14]([CH3:15])[CH3:16])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])=[CH:21][CH:20]=1
Reactant: CC(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1ccc([C@H](C)NC(=O)[C@@H](NC(=O)c2ccccc2)C(C)C)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
(S)-3-Benzoyl-4-isopropyl-2,5-oxazolidinedione (N-benzoyl-L-valine-NCA) (100 mg, 0.40 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (55 mg, 0.40 mmol) and N-methylmorpholine (61 mg, 0.60 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (134 mg, 98%) as white crystals.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:15]([F:18])([F:17])[F:16])([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9][CH2:8]2)[OH:4].[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>C1(C)C(C)=CC=CC=1>[F:17][C:15]([F:18])([F:16])[C:3]([C:2]([F:1])([F:19])[F:20])([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:21](=[O:26])[CH2:22][C:23](=[O:24])[CH3:25])[CH2:10][CH2:9][CH2:8]2)[OH:4]
Reactant: OC(c1ccc2c(c1)CCCN2)(C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Yield: 20.9 %

Procedure:
A stirred mixture of 6.0 g (0.02 mole) of α,α-bis(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol, 2.6 g (0.02 mole) of ethyl acetoacetate, and 100 ml of xylene is refluxed for 16 hours. The mixture is allowed to cool and is evaporated. The residue is triturated with a mixture of toluene, ethyl acetate, and hexane (60:10:30). The insoluble portion is filtered off, washed with water, and dried to give 1.6 g (23%) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol. C. A solution of 10.5 g (0.027 mole) of α,α-bis(trifluoromethyl)-1-(1,3-dioxobutyl)-1,2,3,4-tetrahydro-6-quinolinemethanol in 30 ml of concentrated sulfuric acid is heated on a steam bath for 30-45 minutes, cooled to approximately 60° C., and poured into ice. When the ice is melted, the precipitate is filtered off, washed with water, and dried. The solid is recrystallized from 2-ethoxyethanol to give 7.2 g (74% ) of 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-7-methyl-1H,5H-benzo[ij]quinolizin-5-one, m.p. 295°-296°.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[N:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH:13]([C:11]1[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[N:32][CH:31]=3)[N:3]=[CH:4]2)[N:12]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-isopropyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.66) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.052 g, 24%). MS (ISP) 426.1 [(M+H)+]; mp 277° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([OH:37])[C:34]3[C:29](=[CH:30][C:31]([CH3:38])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:46]([O:50][C:51](=[O:54])[CH2:52]Br)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:24][C:25]([C:27]2[CH:36]=[C:35]([O:37][CH2:52][C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:54])[C:34]3[C:29](=[CH:30][C:31]([CH3:38])=[CH:32][CH:33]=3)[N:28]=2)=[O:26])[CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.8 g of 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 1.2 g of cesium carbonate and 723 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([NH:17][C:18]3([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7](NC(N)=N)=[N:6][CH:5]=1.Cl.Cl.NC1(C(N2CCN(C)CC2)=O)CCCC1.[Cl:53]C1C2C(=CC=C(S(Cl)(=O)=O)C=2)C(Cl)=CN=1>C(Cl)Cl>[Cl:53][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([S:14]([NH:17][C:18]3([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]3)(=[O:16])=[O:15])[CH:9]=2)[C:4]([Cl:3])=[CH:5][N:6]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: CN1CCN(C(=O)C2(NS(=O)(=O)c3ccc4c(Cl)cnc(NC(=N)N)c4c3)CCCC2)CC1
Agent: CN1CCN(C(=O)C2(N)CCCC2)CC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)C2(NS(=O)(=O)c3ccc4c(Cl)cnc(Cl)c4c3)CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16.5 %

Procedure:
4-Chloro-1-guanidino-N-{1-[(4-methylpiperazino)carbonyl]cyclopentyl}-7-isoquinolinesulphonamide dihydrochloride ##STR90## Triethylamine (1.36 ml, 10.0 mmol) was added to a solution of (1-aminocyclopentyl)(4-methyl-1-piperazinyl)methanone dihydrochloride (567 mg, 2.0 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (592 mg, 2.0 mmol) in CH2Cl2 (25 ml), and the reaction stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue partitioned between EtOAc and water, and the layers separated. The organic phase was washed with water, extracted with HCl (2N), and these combined acidic extracts washed with EtOAc, and re-basified using Na2CO3. This aqueous solution was extracted with EtOAc, the combined organic extracts washed with brine, dried (Na2SO4) and evaporated in vacuo to give a foam. This was crystallised from CH2Cl2 -i-Pr2O to afford 1,4-dichloro-N-{1-[(4-methyl-1-piperazinyl)carbonyl]cyclopentyl}-7-isoquinolinesulphonamide (153 mg, 0.33 mmol) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])C.C1CCC(N=C=NC2CCCCC2)CC1.[CH:44]1[C:57]2[C:48](=[N:49][C:50]3[C:55]([C:56]=2[NH:58][C:59]2[CH:60]=[C:61]([NH:67][C:68](=[O:72])[CH:69]([NH2:71])[CH3:70])[CH:62]=[C:63]([CH2:65][OH:66])[CH:64]=2)=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:47]=[CH:46][CH:45]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:54]1[C:55]2[C:50](=[N:49][C:48]3[C:57]([C:56]=2[NH:58][C:59]2[CH:60]=[C:61]([NH:67][C:68]([CH:69]([NH:71][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH3:1])=[O:6])[CH3:70])=[O:72])[CH:62]=[C:63]([CH2:65][OH:66])[CH:64]=2)=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:51]=[CH:52][CH:53]=1
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3ccccc3)CC2)cc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1nc(C)c(C(=O)NC(C)C(=O)Nc2cc(CO)cc(Nc3c4ccccc4nc4ccccc34)c2)cc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.2 %

Procedure:
2-ethyl-6-methoxy-5-[(4-phenylpiperazine-1-carbonyl)amino]nicotinic acid(0.5 g, 1.24 mmole) was dissolved in pyridine(30 mL) and thereto DCC(0.26 g, 1.24 nmole), DMAP(0.15 g, 1.24 mmole) and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide were added. After stirring the resulting mixture for 24 hours at the room temperature. The resulting product was purified by column chromatography to give the titled compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)cc1NCc1ccccc1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of benzyl-(5-fluoro-2-nitrophenyl)amine (3.8 g, 15.2 mmol), iron powder (3.42 g, 60.8 mmol) and ammonium chloride (4.7 g, 91.2 mmol) in methanol (40 mL) and water (10 mL) was heated to 90° C. for 2 h, under an atmosphere of nitrogen. The resultant mixture was diluted with methanol (20 mL) and filtered through Celite®. The Celite® was washed with DCM, methanol and EtOAc (4×) and the filtrate concentrated in vacuo. The residue was partitioned between water (25 mL) and EtOAc (40 mL) and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (25 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a dark brown gum (2.17 g, 66%). The crude material was used without purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.41-7.25 (5H, m), 6.67-6.59 (1H, m), 6.40-6.28 (2H, m), 4.28 (2H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:27])[CH:13]=1)=[CH:5]/[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]([C:23]([F:24])([F:26])[F:25])=[N:21][N:20]=[N:19]2)=[C:14]([Cl:27])[CH:13]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
A solution of nickel (II) chloride hexahydrate (77 mg, 0.324 mmol) and (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid methyl ester (674 mg, 1.62 mmol) in methanol (15 mL) was cooled to 0° C. and then treated with sodium borohydride (184 mg, 4.86 mmol) in four portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 20 h. The reaction mixture was then concentrated in vacuo, and the residue was diluted with water (50 mL) and ethyl acetate (100 mL). The two layers were separated. The organic layer was washed successively with a 3N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-propionic acid methyl ester (640 mg, 95%) as a viscous oil: EI-HRMS m/e calcd for C18H20ClF3N4O2 (M+) 416.1527, found 416.1529.