Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:20](F)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O.C(O)(=O)C>CS(C)=O>[F:1][C:2]1[C:20]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[C:19]([F:22])[C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2c(F)cc3cc4c(=O)c(C(=O)O)cn(C)c4nc3c2F)CC1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
A suspension of 4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 60 cm3 of dimethyl sulphoxide and 3 g of 1-methylpiperazine is heated at 80° C. for 1 hour and a half. After cooling to about 20° C., 150 cm3 of water are added. 18 cm3 of 10% acetic acid are added to the solution obtained. The precipitate formed is drained, washed with 3 times 50 cm3 of water and recrystallized from 50 cm3 of dimethylformamide. 4 g of 7,9-difluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 316° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:34][CH2:33][CH2:31][OH:32])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: NCCO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) was dissolved in THF (4 ml) and a solution of ethanolamine (115 mg, 1.87 mmol) in THF (1 mL) was added. The mixture was stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a light-yellow amorphous solid. mp 120-124°, LC MS m/z=409 (MH+) Retention time=1.84 min.
Reaction SMILES: [C:1]([CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH2:14][CH2:15][N:7]([C:8]=23)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4]1)#[N:2].[H-].C([Al+]CC(C)C)C(C)C.[H-].CO>ClCCl>[CH2:15]1[N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[CH:3]([CH2:1][NH2:2])[NH:4][C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=32)[CH2:14]1
Reactant: N#CC1Nc2ccccc2N2CCc3cccc1c32
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: NCC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 3 h
Yield: 50.5 %

Procedure:
6-Cyano-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (15 g) was added to 300 ml of a 1M solution of diisobutylaluminium hydride in dichloromethane at -78° C. The reaction mixture was stirred for 3 hours at low temperature and thereafter diluted to 1 liter with dichloromethane. The excess hydride was slowly decomposed with methanol (50 ml). The gelatinous solution was washed with 5% sodium hydroxide (500 ml) and brine (2×500 ml) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to a solid-oil mixture (15.2 g). Purification was effected by flash chromatography over silica gel (145 g, eluted with 3.5% methanol/dichloromethane) to afford 7.7 g of product. Recrystallization from hot ethanol (65 ml) yielded 6.2 g of crystals, m.p. 171.5°-172.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:24]1([CH3:42])[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=[C:32]([C:38]([F:41])([F:40])[F:39])[N:31]=2)[CH:25]=1>C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH:37][CH2:36][C:35]2[C:30]([C:26]3[CH:25]=[C:24]([CH3:42])[CH:29]=[CH:28][CH:27]=3)=[N:31][C:32]([C:38]([F:41])([F:39])[F:40])=[CH:33][CH:34]=2)=[O:23])[CH:5]=[CH:6][C:7]=1[CH2:8][NH:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)ccc1CNS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)Nc2ccc(CNS(C)(=O)=O)c(C)c2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 87.9 %

Procedure:
To a stirred solution of phenyl 3-methyl-4-(methylsulfonamidomethyl)-phenylcarbamate (46 mg, 0.137 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (36 mg, 0.137 mmol) in acetonitrile were added 4-dimethylaminopyridine (17 mg, 0.137 mmol). The reaction mixture was stirred for 15 h at 50° C. The mixture dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. N-(2-Methyl-4-(3-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)ureido)benzyl)methanesulfonamide (example 81) (61 mg) was obtained as 88% yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)[C:8]([CH3:18])=[CH:7][C:5]=2[N:6]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[Cl:19])=[O:23])=[N:15][CH:16]=3)[C:8]([CH3:18])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C)c(-c3ccc(N)nc3)cc2o1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(C)c(-c3ccc(NC(=O)c4ccccc4Cl)nc3)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 5-(2,5-dimethylbenzoxazol-6-yl)-2-pyridylamine (49) (42 mg, 0.175 mmol) in 2 ml DCM was added 2-chlorobenzoyl chloride (44 μl, 2 eq) followed by addition of DIEA (153 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (350 μl) at r.t. for 4 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 47.7 mg N-[5-(2,5-dimethylbenzoxazol-6-yl)(2-pyridyl)](2-chlorophenyl)carboxamide (50) as white solid. (yield: 72.1%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].C(N(CC)CC)C.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20].[Na]>C(#N)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([O:3][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
Under nitrogen, 17.7 g (128 mmol) of 4-fluoroacetophenone (Aldrich) and 20.7 mL (192 mmol) of triethylamine at ambient temperature was treated with 24.4 mL (192.3 mmol) of chlorotrimethylsilane and allowed to stir of 20 minutes prior to the slow addition of a suspension of 30 g (200 mmol) of sodium iodode in 200 mL of acetonitrile. The extracts were combined, dried (K2CO3), and concentrated in vacuo to give 27 g of crude 1-fluoro-4-[1[(trimethylsilyl)oxy]ethenyl]benzene as an oil: NMR (CDCl3) δ 0.28 (s, 9H), 4.41 (d, J=2 Hz, 1H), 4.84 (d, J=2 Hz, 1H), 7.00 (d, J=8 Hz, 2H), 7.53 -7.60 (m, 2H).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>C(Cl)Cl>[C:1]1([O:7][C:8](=[O:9])[NH:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chloroformic acid phenyl ester (3.29 g, 21.0 mmole) and pyridine (1.74 g, 22.0 mmole) were added to a solution of tryptamine (3.2 g, 20.0 mmole) in CH2Cl2 and stirred for 24 h at room temperature. Working up was performed by extracting the batch successively with water, with 1M HCl and with 1M NaOH. The organic phase was dried with Na2SO4 and evaporated. The product was obtained as a colorless solid (m.p. 44-46° C.) in a yield of 5.58 g (100%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([NH:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[CH2:42][CH2:43][CH2:44][C@@H:37]12.[C:45](=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:16]([N:18]([C:19]3[CH:20]=[N:21][C:22]([N:41]4[CH2:40][CH2:39][N:38]5[CH2:42][CH2:43][CH2:44][C@H:37]5[CH2:36]4)=[CH:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[CH3:32])[CH3:45])=[O:17])[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1NC(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCC[C@H]3C2)ncc1N(C)C(=O)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 150 °C
Yield: 61.7 %

Procedure:
The title compound was prepared starting from 100 mg (0.188 mmoles) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]cyclopropanecarboxamide (D2), 70 mg (0.554 mmol) of (8aS)-octahydropyrrolo[1,2-a]pyrazine, 52.2 mg (0.377 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100%, affording 72 mg of the title compound as pale yellow solid.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][N:13]=[C:14]=[S:15]>O1CCOCC1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[CH2:12][NH:13][C:14]([NH:2][NH2:3])=[S:15]
Reactant: Fc1ccc(Br)c(CN=C=S)c1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNC(=S)NCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of hydrazine hydrate (80%, 2.22 g, 35.5 mmol) in 1,4-dioxane (20 mL) at 0° C. was added a solution of 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (13, 3.16 g, 12.8 mmol) in 1,4-dioxane (5 mL) The mixture was stirred at RT for 2 h. Ice cold water (100 mL) was added. The precipitated solid was collected by filtration, washed with water, and dried over P2O5 overnight to provide N-(2-bromo-5-fluorobenzyl)hydrazinecarbothioamide (14). MS: m/z, 278 (100%, M+1), 280 (100%), 300 (10%, M+23), 302 (10%).
Reaction SMILES: CO[C:3](OC)(OC)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]1([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:27][CH:26]=[CH:25][CH:24]=2>C1(C)C=CC=CC=1>[CH2:4]([C:3]1[N:30]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Temperature: 25 °C

Procedure:
Trimethylorthovalerate (1.8 mL, 10.4 mmol) and pyridine hydrochloride (92 mg, 0.8 mmol) were added to a suspension of 4-[(3-aminoquinolin-4-ylamino)methyl]tetrahydropyran-4-ol (8.0 mmol) in toluene (40 mL). The reaction mixture was heated at reflux for 2.5 hours and then cooled to ambient temperature. A precipitate was isolated by filtration and dried to provide 4-[(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 180-181° C. MS (ESI) m/z 340 (M+H)+; Anal. calcd for C20H25N3O2: C, 70.77; H, 7.42; N, 12.38. Found: C, 70.58; H, 7.53; N, 12.40.
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3.[CH3:24][S-:25].[Na+]>[Cu]Br>[CH3:24][S:25][C:2]1[C:7]2[C:8](=[O:23])[C:9]3[C:10]([CH:21]=[CH:22][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[N:11][CH:12]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:14]=3
Reactant: O=c1c2cc(-c3ccccc3)cnc2ccc2cccc(Br)c12
Reactant: C[S-]
Agent: [Cu]Br
Agent: [Na+]
Product: CSc1cccc2ccc3ncc(-c4ccccc4)cc3c(=O)c12
Temperature: 140 °C
Reaction time: 72 h

Procedure:
6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (15 mg, 0.04 mmol), sodium thiomethoxide (15 mg, 0.21 mmol) and copper (1) bromide (23 mg, 0.10 mmol) were combined in a dry flask. The flask was purged with argon and 0.5 mL of N,N-dimethylformamide were added. The solution was stirred and heated to 140° C. After 72 h, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with 5% HCl, brine and water. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.14 (d, 1H), 8.58 (d, 1H), 7.78 (d, 2H), 7.65 (m, 2H), 7.54 (t, 2H), 7.47 (m, 3H), 7.27 (d, 1H), 2.49 (s, 3H). LRMS (APCI) calculated for C21H16NOS [M+H]+, 330.0; found 330.1
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C[O:12][CH2:11]C1.[F:14][C:15]([F:33])([F:32])[C:16]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[N:17]=1.C(N(CC)CC)C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:11]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([N:18]3[C:19]([C:21]([F:22])([F:23])[F:24])=[CH:20][C:16]([C:15]([F:14])([F:32])[F:33])=[N:17]3)=[CH:26][CH:27]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: Clc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Chlorobenzol chloride (88 mg) and THF (2 ml) were added to a mixture of 4-[3,5-bis(trifluromethyl)-1H-pyrazol-1-yl]aniline (150 mg), triethylamine (57 mg) and THF (2 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1 N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, 4-chloro-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]benzanilide (105 mg) was obtained as colorless powder crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]([CH2:18][CH3:19])[C:15](=[O:20])[C:14]([C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=3[CH3:30])[C:24]([OH:26])=O)=[N:13][C:12]=2[CH:11]=[N:10]1.C(Cl)(=O)C(Cl)=O.[NH2:38][C:39]1[CH:43]=[CH:42][O:41][N:40]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]([CH2:18][CH3:19])[C:15](=[O:20])[C:14]([C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=3[CH3:30])[C:24]([NH:38][C:39]3[CH:43]=[CH:42][O:41][N:40]=3)=[O:26])=[N:13][C:12]=2[CH:11]=[N:10]1
Reactant: Nc1ccon1
Reactant: CCn1c(=O)c(-c2cc(C(=O)O)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(C(=O)Nc3ccon3)cc(F)c2C)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid (360 mg, 0.84 mmol) in 5.0 mL of DCM was treated with oxalyl chloride (0.84 mL of 2.0 M in DCM solution, 1.68 mmol) followed by two drops of DMF while cooling in an ice bath at 0° C. It was stirred at this temperature for 15 min then allowed to stir at RT for 45 min. The reaction mixture was then concentrated under reduce pressure to remove the excess oxalyl chloride. The residue was dissolved in 5.0 mL of DCM, treated with 3-aminoisoxazole (212 mg, 2.52 mmol) followed by Et3N (0.18 mL, 1.26 mmol) and stirred for 18 h. The reaction mixture was treated with 15 mL saturated NaHCO3 and extracted with DCM (2×15 mL). The combined DCM layers were dried over MgSO4. Purification on the ISCO (12 g column, 20-70% EtOAc in hexanes) afforded 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide as a light yellow amorphous solid. MS (ES+): 495.1 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH2:23][C:24](=[O:28])[NH:25]3)=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>C(O)C.N1CCCCC1>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([C:19]2[CH:27]=[C:26]3[C:22]([C:23](=[CH:34][C:30]4[NH:29][CH:33]=[CH:32][CH:31]=4)[C:24](=[O:28])[NH:25]3)=[CH:21][CH:20]=2)=[O:18])[CH:13]=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)ccc2C1=Cc1ccc[nH]1

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:12]1[CH2:11][CH2:10][C@H:9]2[C@H:14]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][C:6]=3[C:7](=[O:15])[CH2:8]2)[CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Product: O=C1C[C@H]2CCN(Cc3ccccc3)C[C@H]2c2ccc(F)cc21

Procedure:
In an analogous manner to that described in Example 49 b), from cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one by alkylation with benzyl bromide there was obtained cis-2-benzyl-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with MeOH/HCl into the hydrochloride with m.p. >220°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.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>[O:9]1[CH:13]=[CH:12][C:11]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:10]1
Reactant: OB(O)c1ccoc1
Reactant: Nc1cnc(Br)cn1
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: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccoc2)cn1
Yield: 92.5 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.294 mmol), furan-3-boronic acid acid (300 mg, 2.681 mmol), and a saturated aqueous sodium carbonate solution (2 mL) in ethylene glycol dimethyl ether (5 mL) and ethanol (5 mL) was heated under reflux for 45 min. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/3 hexanes/ethyl acetate to ethyl acetate) afforded 5-furan-3-yl-pyrazin-2-ylamine (256.9 mg, 92.5%) as a yellow solid: LRMS for C8H7N3O (M+H)+ at m/z=162.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.Cl[C:28]([O:30][CH3:31])=[O:29]>>[CH3:31][O:30][C:28](=[O:29])[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield according to the general procedure for the preparation of carbamates (Method D) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and methyl chloroformate.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2nc[nH]c12)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A mixture of (S)-1-(5-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 29 (379 mg, 1.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (340 mg, 1.4 mmol) and DIPEA (1.2 mL, 7.0 mmol) in n-butanol (7 mL) was stirred in a sealed vial for 18 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 161 (65 mg, 12%). LCMS: RT 3.34 min [M+H]+ 374.1. 1H NMR (DMSO, 400 MHz): δ 8.19-8.00 (2H, m), 7.92 (1H, s), 7.67-7.41 (6H, m), 7.06 (2H, d, J=7.13 Hz), 5.47 (1H, s), 1.56 (3H, d, J=6.83 Hz)