Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:62][N:63]2[CH2:84][C:83]3[N:85]=[C:79]([CH:80]=[CH:81][CH:82]=3)[CH2:78][N:77](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:76][CH2:75][N:74](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:73][C:72]3[N:106]=[C:68]([CH:69]=[CH:70][CH:71]=3)[CH2:67][N:66](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:65][CH2:64]2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:29][C:28]3[N:30]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][C:17]3[N:51]=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH2:12][N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.OS(O)(=O)=O.[OH-].[Na+].[BrH:124]>CCO>[BrH:124].[BrH:124].[BrH:124].[BrH:124].[BrH:124].[BrH:124].[BrH:124].[BrH:124].[C:4]1([CH2:7][N:8]2[CH2:29][C:28]3[N:30]=[C:24]([CH:25]=[CH:26][CH:27]=3)[CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]3[N:51]=[C:13]([CH:14]=[CH:15][CH:16]=3)[CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][C:1]([CH2:62][N:63]2[CH2:84][C:83]3[N:85]=[C:79]([CH:80]=[CH:81][CH:82]=3)[CH2:78][NH:77][CH2:76][CH2:75][NH:74][CH2:73][C:72]3[N:106]=[C:68]([CH:69]=[CH:70][CH:71]=3)[CH2:67][NH:66][CH2:65][CH2:64]2)=[CH:2][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)Cc3cccc(n3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(Cc3ccc(CN4CCN(S(=O)(=O)c5ccc(C)cc5)Cc5cccc(n5)CN(S(=O)(=O)c5ccc(C)cc5)CCN(S(=O)(=O)c5ccc(C)cc5)Cc5cccc(n5)C4)cc3)Cc3cccc(n3)C2)cc1
Agent: Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: c1cc2nc(c1)CNCCN(Cc1ccc(CN3CCNCc4cccc(n4)CNCCNCc4cccc(n4)C3)cc1)Cc1cccc(n1)CNCCNC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of 17,17'-[1,4-phenylenebis(methylene)]bis[3,6,14-tris(p-toluenesulphonyl)-3,6,14,17,23,24-hexaazatricyclo[17.3.1.18,12 ]tetracosa-1(23),8,10,12(24),19,21-hexaene] (280 mg, 0.166 mmol) in cone H2SO4 (2 ml) was stirred at 110° C. for 2 hours. The dark brown solution was cooled to room temperature and the pH adjusted to 14 with the addition of 10N NaOH. The aqueous phase was extracted with CHCl3 (20 ml, x 3), the combined organic phases were dried over MgSO4 and concentrated in vacuo thus affording a pale yellow oil. To a stirred solution of the oil in 10 ml of anhydrous EtOH was passed HBr(g) resulting in a white solid precipitate. After stirring for 15 minutes at room temperature the solid was filtered off, washed with ether and dried in vacuo giving 17,17'-[1,4-phenylenebis(methylene)]bis-3,6,14,17,23,24-hexaazatricyclo-[17.3.1.18,12 ]tetracosa-1(23),8,10,12(24),19,21-hexaene octahydrobromide (135 mg, 58%) as a white solid. 1H NMR (D2O) δ 3.73 (s, 8H), 3.94 (s, 8H), 4.38 (s, 8H), 4.45 (s, 8H), 6.86 (d, 2H, J=8.6 Hz), 7.19-7.24 (m, 6H), 7.47 (d, 4H, J=8.6 Hz), 7.56 (t, 2H, J=8.6 Hz), 7.87 (t, 2H, J=8.6 Hz). 13C NMR (D2O) δ 44.86, 46.77, 47.03, 53.41, 53.66, 56.18, 60.24, 124.83, 125.00, 125.06, 125.85, 132.32, 134.83, 141.99, 142.06, 152.20, 152.31, 152.41. Mass spectrum (FAB); m/e (relative intensity); 838 (M+HBr, 4), 836 (M+HBr, 4), 756 (M+1, 14), 429 (20), 307 (60), 215 (100). C44H66N12 Br8 requires C, 37.68; H, 4.74; N, 11.98; Br, 45.58; Found: C, 37.86; H, 4.94; N, 11.90; Br, 45.33.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pt]
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1N

Procedure:
The title compound was prepared from [2-nitro-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example A13) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a light brown solid (13.157 g).
Reaction SMILES: CCOCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[F:15][C:16]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19]>C1COCC1>[F:15][C:16]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[O:19]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1F
Temperature: 50 °C
Yield: 0.7 %

Procedure:
2M Et2O solution of 4-fluorophenylmagnesium bromide (32.5 ml; 65 mmol) was added to a solution of 12.8 g (65 mmol) of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide in 150 ml of THF at 0° C. The reaction mixture was heated overnight at 50° C. The reaction mixture was partitioned with EtOAc and H2O. The organic phases were washed with brine and dried over Na2SO4. The resulting ketone (135 mg) was obtained after flash chromatographic purification using hexane/CH2Cl2 (3:1, v/v) as an eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Temperature: 75 °C
Yield: 54.3 %

Procedure:
A mixture of 5-nitroindazole (40.75 g, 250 mmol), picolyl chloride hydrochloride (45.1 g, 275 mmol) and potassium carbonate (72.4 g, 525 mmol) in DMF (400 ml) was heated at 75° C. for 3 hours. Additional picolyl chloride hydrochloride (4.1 g, 25 mmol) and potassium carbonate (3.45 g, 25 mmol) were added and the mixture was heated at 75° C. for 2 additional hours. After cooling, the mixture was diluted with water (800 ml). The precipitate was filtered, washed with water and dried. The resulting solid was purified by chromatography on silica gel (eluant: 50% ethyl acetate in petroleum ether) to give 5-nitro-1-(pyridin-2-ylmethyl)-1H-indazole as a solid (34.5 g, 55%); NMR Spectrum (CDCl3) 5.77 (s, 2H), 7.03 (d, 1H), 7.23 (m, 1H), 7.55 (d, 1H), 7.63 (m, 1H), 8.27-8.23 (m, 2H), 8.58 (m, 1H), 8.74 (d, 1H); Mass spectrum MH+ 255.
Reaction SMILES: [CH:1]1([C:4]2[NH:9][C:8](=O)[CH:7]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)[nH]1
Product: FC(F)(F)c1ccc(-c2cc(Cl)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-1H-pyridin-2-one (5.0 g, 18 mmol) and phosphoryl chloride (8.2 mL, 90 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as an off-white solid (4.73 g, 88%). MS (ISP) 298.2 [(M+H)+] and 300 [(M+2+H)+].
Reaction SMILES: [N:1]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[CH:3][C:2]=1[CH:9]=O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[NH2:14]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[N:14]=[CH:9][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:7]=[N:14][C:13]2[C:12]([Cl:11])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:1]=1
Reactant: O=Cc1cccc(C=O)n1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1N=Cc1cccc(C=Nc2c(Cl)cccc2Cl)n1

Procedure:
2,6-Pyridinedicarboxaldehyde (1 g, 7.4 mmol) and 2,6-dichloroaniline (2.6 g, 16.0 mmol) were dissolved in 100 ml of toluene. To this solution 4 Å molecular sieves were added. After standing for 2 days, with addition of more 4 Å molecular sieves the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 1.4 g (45%) of 6. 1H-NMR (CDCl3) δ 8.53 (s, 2H, HC═N), 8.45 (d, 2H, Py-Hm), 8.02 (t, 1H, Py-Hp), 7.36 (d, 4H, ArH), 7.03 (t, 2H, ArH).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:4]1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:2][N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:23]3[CH:22]=[N:21][CH:20]=[C:19]([F:18])[CH:24]=3)=[N:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:4]1
Reactant: Fc1cncc(F)c1
Reactant: Cn1ccc(NC(=O)c2nccnc2N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2nccnc2Nc2cncc(F)c2)n1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
3-Amino-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (120 mg, 0.47 mmol), 3,5-difluoropyridine (500 mg, 4.4 mmol), cesium carbonate (610 mg, 1.89 mmol) and 1 mL N,N-dimethylformamide were mixed and stirred under microwave irradiation for 60 minutes at 180° C. The reaction mixture was extracted with sat. NaHCO3— solution and three times ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->30:70 gradient). The desired compound was obtained as a yellow solid (24 mg, 16%), MS: m/e=314.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: Cc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of tert-butyl {1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1 (200 mg, 0.440 mmol, 1.0 eq) in DCM (2.2 mL) and methanol (1.8 mL) was added a solution of 4 M hydrogen chloride in dioxane (2.2 mL, 8.80 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 130 mg (83% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=CC=1.CI>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1C=Nc2c(Cl)cccc21
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1CS(=O)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
4-Chlorobenzothiazolone (9.28 g, 0.05 mole) was dissolved in a solution of sodium hydroxide (3.19 g, 0.075 mole) in water (220 ml), and tetra-n-butylammonium bromide (0.48 g, 0.0015 mole) and toluene (80 ml) were added thereto. Methyl iodide (11.21 g, 0.075 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 30 minutes and then at 50° to 60° C. for 1 hour, followed by cooling and phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 9.58 g of 4-chloro-N-methylbenzothiazolone as pale yellow crystals. Yield 96.0%, purity 99.3%, m.p. 130°-132° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[C:14]([CH2:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:15]>>[C:14]([CH2:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:7]=[C:6]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([CH2:16][C:14]#[N:15])=[CH:18][CH:19]=3)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=2)=[CH:19][CH:18]=1)#[N:15]
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Reactant: N#CCc1ccc(N)cc1
Product: CCOC(=O)c1cnc(Nc2ccc(CC#N)cc2)nc1Nc1ccc(CC#N)cc1

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine, 2,4-dichloro-5-ethoxycarbonylpyrimidine and 4-cyanomethylaniline were reacted to yield N2,N4-bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.72 (s, 1H), 7.64 (m, 4H), 7.32 (d, 2H, J=8.7 Hz), 7.21 (d, 2H, J=8.4 Hz), 4.3 (q, 2H, J=7.0 Hz), 3.97 (s, 2H), 3.89 (s, 2H), 1.32 (3H, J=7 Hz); LCMS: ret. time: 30.83 min.; purity: 90%; MS (m/e): 413 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CCO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:48][CH2:47][CH2:46][CH2:45][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:34])[C:15]1=[O:38].[N:39]1([CH2:45][CH2:46][CH2:47][NH2:48])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NCCCN1CCOCC1
Solvent: CCO
Product: O=C(NCCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (2.5 mL) under nitrogen was treated with [3-(4-morpholinyl)propyl]amine (0.035 mL, 0.24 mmol) for 40 min.@130° C. in a microwave vessel. The reaction was then cooled to ambient temperature and the resulting suspension was filtered, washed with EtOH and Et2O then thoroughly dried under high vacuum to provide the title compound as a white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.5 (m, 4 H), 2.2 (t, J=7.0 Hz, 2 H), 2.3 (m, 1 H), 2.6 (t, J=6.9 Hz, 2 H), 3.2 (q, J=6.5 Hz, 2 H), 3.5 (q, J=4.9 Hz, 8 H), 3.9 (t, J=5.5 Hz, 2 H), 4.1 (s, 2 H), 4.5 (t, J=5.6 Hz, 2 H), 7.1 (ddd, J=9.1, 6.7, 2.1 Hz, 2 H), 7.3 (m, 2 H), 7.8 (m, 4 H), 8.1 (s, 1 H), 8.4 (t, J=1.1 Hz, 1 H), 10.0 (t, J=6.0 Hz, 1 H); ES+ MS: 614 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:17])[C:15]#[N:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:16][CH2:15][CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)=[O:7])[CH2:9][CH2:10]1)[CH3:17]
Reactant: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)N1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 100 %

Procedure:
A mixture of 32 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia is hydrogenated in the Parr-apparatus at 25° C. with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylbenzene and the latter is evaporated again. The residue is dissolved in 2,2'-oxybispropane and the solution is filtered till clear. The solvent is evaporated, yielding 32 parts (100%) of [1-(2-amino-1-methylethyl)-4-piperidinyl](4-fluorophenyl)methanone as an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:17]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[NH:7][C:8](=[O:14])[C:9]([O:11][CH2:12][CH2:13][CH3:17])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1O
Solvent: CCCO
Product: CCCOC(=O)C(=O)Nc1cc(Cl)ccc1O
Temperature: 100 °C
Reaction time: 48 h
Yield: 300.7 %

Procedure:
A mixture of 2.5 g of ethyl 5-chloro-2-hydroxyoxanilate, 200 mg of p-toluenesulfonic acid, and 100 ml of n-propanol was stirred for 2 days at 100° C. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and recrystallized from n-propanol to provide 0.9 g of n-propyl 5-chloro-2-hydroxyoxanilate.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:43]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:17][C:18]2[C:23]3[N:24]=[C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[S:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.ClCCl>>[NH2:43][C@@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:11][CH:10]=1)[C:14]([N:16]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:17][C:18]1[C:23]2[N:24]=[C:25]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[S:26][C:22]=2[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(CN(Cc1cccc2sc(NC(=O)OC(C)(C)C)nc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2sc(NC(=O)OC(C)(C)C)nc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(2-tert-butoxycarbonylaminobenzothiazole-4-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-1) (482 mg, 0.58 mmol) was added 25%-piperidine/dichloromethane (4 ml) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (353.2 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([C:38]([NH2:40])=[O:39])=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[CH:34][C:35]([C:38]([NH2:40])=[O:39])=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2ccc(C(N)=O)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(N)=O)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid amide (Stage 14.1.1, 106 mg, 0.427 mmol) to give the title compound as a lightly yellow solid. (HPLC: tR 2.28 min (Method A); M+H=414 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.73-8.67 (m, 1H), 8.22-8.04 (m, 5H), 8.03-7.98 (m, 1H), 7.71-7.61 (m, 2H), 3.92 (s, 3H), 3.59 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](I)[CH:25]=[CH2:26].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:26][CH:25]=[CH2:24])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To the solution was added 0.6 g of approximately 50 % sodium hydride and stirring was performed for 30 minutes. To this was added 3.4 g of allyl iodide and the mixture was reacted for 3 hours at room temperature. Then the solvent was evaporated from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.3 g of 1-(m-nitrophenyl)-3-allylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 188-189°C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:12]=[CH:11][C:9]([N:10]=[N:10][C:9]3[CH:11]=[CH:12][C:6]([OH:5])=[CH:7][CH:8]=3)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(OCC2CC2)ccc1N=Nc1ccc(O)cc1
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a mixture of 4-(cyclopropylmethoxy)-2-nitroaniline (416 mg) and ethanol (2 mL) was added 6M hydrochloric acid (1.5 mL), and ethanol was evaporated under reduced pressure. To the obtained suspension was added a mixture of sodium nitrite (145 mg) and water (1 mL) under ice-cooling, and the mixture was stirred for 30 min. A mixture of phenol (245 mg) and 8M aqueous sodium hydroxide solution (1.2 mL) was added thereto, and the mixture was stirred for 1 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a dark red solid (187 mg).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1>O1CCOCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=[CH:14]2)=[CH:5]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: C1COCCO1
Product: c1ccc2c(c1)ncn2CCc1c[nH]c2ccccc12

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.48 g, 20 mmol) and benzimidazole (4.72 g, 40 mmol) in abs. dioxane (50 ml) was stirred at 90° C. for 13 h. The solvent was then removed i. vac., CHCl3 (200 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (40:1). Yield: 1.32 g (25%), pale brown solid