Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:12])[F:13])[N:7]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])[C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C(F)F)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Reaction time: 0.33 h
Yield: 106.5 %

Procedure:
To a 100 mL round bottomed flask containing DMF (17 mL) was added 4-bromo-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (2.3 g, 7.88 mmol), 1-(bromomethyl)-3-chloro-2-methylbenzene (2.4 g, 10.93 mmol) and potassium carbonate (2.3 g, 16.64 mmol). The resultant suspension was heated to 70° C. and after stirring for 20 minutes LC/MS indicated that almost all starting material had been consumed so the heat was turned off and the reaction was allowed to stir overnight at rt. The next day the mixture was diluted with 75 mL H2O and stirred for 10 minutes resulting in the precipitation of a light brown solid. The solid was isolated by filtration and was washed 3× with H2O and 3× with hexanes to provide 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (4.2 g, 8.39 mmol, 107% yield) as light brown solid. The NMR and LC/MS were consistent with desired product and the crude product will be used in subsequent reactions without further purification. LC/MS: MS (ES+) m/e 431.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (d, J=2.02 Hz, 1H), 8.45 (d, J=2.02 Hz, 1H), 7.32-7.68 (m, 2H), 6.99-7.12 (m, 1H), 6.06 (d, J=7.58 Hz, 1H), 5.90 (s, 2H), 2.47 (s, 3H)
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[CH3:37][O:38][CH2:39][CH2:40][NH:41][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: COCCN
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Product: COCCNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-methoxyethylamine according to Procedure K: mp>230° C.; Anal. Calcd for C18H19N5O5S: C, 51.79; H, 4.59; N, 16.78. Found: C, 51.69; H, 4.54; N, 16.72.
Reaction SMILES: [CH:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:14]=[O:15]>C1(C)C=CC=CC=1>[CH:1]([C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:14]=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=O
Reactant: CCCCC=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: CCCCC=Cc1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a stirred solution of Mg(OMe)2 (8% by weight in methanol 16.88 ml, 12.76 mM) was added 2-(1-hexenyl)phenol (3.44 g, 19.5 mmol) in toluene (18 ml). The reaction mixture was warmed to reflux and held at reflux for 2 hours. Toluene (18 ml) was added and the solvent distilled off until the reaction temperature rose to 93° C. A slurry of paraformaldehyde (1.8 g, 60 mmol) in toluene (18 ml) was added and the reaction heated at reflux for 3 hours. The reaction was allowed to cool to ambient temperature and stirred overnight. The reaction was diluted with toluene (20 ml) and washed with 2M aqueous H2SO4 (20 ml). The organic phase was washed with water until the aqueous phase was neutral in pH, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl ether/hexane) to give 3-(1-hexenyl)-2-hydroxybenzaldehyde (2.32 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:24]=3)[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: CO
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)c3ccc(F)cc3)CC2)c1

Procedure:
Example 42 was prepared from 2-(4-fluoro phenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 2H), 7.32–7.22 (m, 4H), 7.01–6.92 (m, 3H), 6.90–6.83 (m, 1H), 3.50 (q, 1H, J=7.1 Hz), 3.39–3.26 (m, 2H), 2.93–2.86 (m, 1H), 2.55–2.42 (m, 2H), 2.40–2.34 (m, 2H), 2.16 (s, 1H), 2.01–1.91 (m, 2H), 1.89–1.77 (m, 2H), 1.72–1.54 (m, 4H), 1.49 (d, 3H, J=7.0 Hz), 1.24 (d, 6H, J=7.0 Hz); ESMS m/e: 454.3 (M+H)+; Anal. Calc. for C27H36FN3O2.1.1 CH3OH: C, 69.04; H, 8.33; N, 8.60. Found: C, 69.06; H, 8.61; N, 8.79.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([NH:11][C:19](=[O:20])[O:21][CH3:22])[CH3:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(N)Cc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromophenyl)propan-2-amine (0.5 g, 2 mmol) in methylene chloride (5 mL) was added pyridine (380 uL, 4.7 mmol) and methyl chloroformate (270 uL, 3.5 mmol, Aldrich, Cat. No. M35304). The reaction mixture was stirred at r.t. overnight, and concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with NaHCO3 aqueous solution, 1N HCl aqueous solution and brine. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatograph on a silica gel column using 25% Ethyl acetate in hexane to afford the desired compound. LCMS (M+H)+: m/z=272.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(=O)C.[K+].O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:9]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1sccc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(-c2ccccc2)cc1C
Temperature: 150 °C
Yield: 4.5 %

Procedure:
At room temperature, a solution of 4-iodobenzene (9.6 mmol) and methyl 3-methylthiophene-2-carboxylate (19.2 mmol) in dimethylacetamide (20 ml) were degassed with nitrogen for 15 minutes. Potassium acetate (0.87 mmol) and palladium acetate (0.02 mmol) were added, the reaction vessel was sealed and heated at 150° C. for 1 hour. Then, the reaction mixture was cooled down to room temperature and poured into water, extracted with dichloromethane, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: gradient of 3% diethyl ether in petroleum ether) to give 100 mg of Intermediate V.1 (22%) as a yellow solid, which was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.57 (s, 3H), 3.88 (s, 3H), 7.13 (s, 1H), 7.32-7.34 (m, 3H), 7.59-7.64 (m, 2H); and MS (ESI, EI+) m/z=233 (MH+).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([F:14])[CH:8]=1)(=O)=O.N1C(C)=CC=C[C:16]=1C>CO.CCOCC>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][O:5][CH3:16])=[CH:8][C:9]=1[F:14]
Reactant: CS(=O)(=O)OCc1ccc(Br)c(F)c1
Reactant: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: CO
Product: COCc1ccc(Br)c(F)c1

Procedure:
A solution of 4-bromo-3-fluorobenzyl methanesulfonate (Intermediate 18, 286 mg; 1.01 mmol) and 2,6-lutidine (234 μL; 2.0 mmol) in methanol (4 mL) was stirred for 16 hours at RT. Additional aliquots of 2,6-lutidine (234 μL; 2.0 mmol each) were added once a day for a total of three days, during which stirring was continued at RT. The mixture was taken up in Et2O, washed with water, HCl (0.1N in water) and brine. The organic phase was dried over MgSO4, filtered and concentrated with moderate vacuum and without heating affording the title compound in a mixture with ethyl ether.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[CH3:22][C:20]1[N:21]=[C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[S:18][CH:19]=1
Reactant: Cc1csc(-c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)n1
Agent: Cl
Product: Cc1csc(-c2ccc3c(c2)CNC3)n1

Procedure:
Prepared in analogy to Example A3(e) from 5-(4-Methyl-thiazol-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and using trifluoacetic acid instead of hydrochloride acid. Brown solid. MS (m/e): 217.1 ([M+H]+, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH3:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[C:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[CH:26]=3)[CH2:33][CH2:34]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 82 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:26])[N:4]([CH3:25])[CH:5]=[C:6]([C:8]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=2[Cl:19])[CH3:10])[CH:7]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[C:3](=[O:26])[N:4]([CH3:25])[CH:5]=[C:6]([C:8]([OH:24])([C:20]([F:22])([F:23])[F:21])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:19])[CH3:10])[CH:7]=1
Reactant: COc1ccc(C(C)C(O)(c2cc(Cl)c(=O)n(C)c2)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Product: CC(c1ccc(O)cc1Cl)C(O)(c1cc(Cl)c(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 147, step 5, 3-chloro-5-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with BBr3 to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=393.8 [M−H+].
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:48]([O:47][C:45]([N:42]1[CH2:43][CH2:44][CH:39]([N:19]2[C:20]3[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:40][CH2:41]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ccc(OC(F)F)cc34)nc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A pressure tube was charged with 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (180 mg, 0.34 mmol), tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol), cesium carbonate (332 mg, 1.02 mmol) and DMF (1.5 ml). The tube was flushed with argon, sealed and stirred at 100° C. in an oil bath overnight. The reaction was cooled to room temperature and additional tert-butyl 4-bromopiperidine-1-carboxylate (179 mg, 0.68 mmol) and cesium carbonate (332 mg, 1.02 mmol) were added. The tube was again flushed with argon, sealed and stirred at 100° C. in an oil bath for 6 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 25 g silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 197 mg (81%) of 4-{3-[7-tert-butylcarbamoyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-5-difluoromethoxy-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[OH-].[NH4+].[H][H]>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH2:9])[CH:2]=1
Reactant: [H][H]
Reactant: N#CCc1cccnc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCc1cccnc1
Yield: 90.8 %

Procedure:
A mixture of 2-(pyridin-3-yl)acetonitrile (1 g, 8.47 mmol, 1.00 equiv), Raney nickel (1 g, 17.24 mmol, 1.00 equiv) and ammonium hydroxide (3 mL) in methanol (15 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight. The catalyst was removed by filtration through a pad of Celite and washed with several portions of methanol. The filtrate and washings were combined and concentrated under vacuum to give 940 mg (45%) of 2-(pyridin-3-yl)ethanamine as a yellow oil. LC-MS: (ES, m/z): 164 [M+CH3CN+H]+, 123 [M+H]+, 106.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=O)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[C:17]([Cl:22])=[O:19])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=Cc1ccc(C(=O)O)c(SCc2ccccc2)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)c(SCc2ccccc2)c1

Procedure:
To a solution containing 23.2 g of 3-benzylmercapto-4-carboxy benzaldehyde in 250 ml of methylene chloride is added 15 ml of thionyl chloride and 0.5 ml of dimethylformamide. The reaction mixture is refluxed for 6-7 hours, then evaporated to dryness. Crystallization from 100 ml of ether yielded 27.0 g of 3-benzylmercapto-4-chlorocarbonyl benzaldehyde (a).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([NH2:28])[CH2:12][C:11]1=[O:29]>C1C=CC=CC=1>[CH3:9][N:10]1[C:16]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]([N:28]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][C:11]1=[O:29]
Reactant: CN1C(=O)CN(N)C(c2ccccc2)c2cc(Cl)ccc21
Reactant: O=Cc1ccccc1
Solvent: c1ccccc1
Product: CN1C(=O)CN(N=Cc2ccccc2)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 80.7 %

Procedure:
1 ml. (9.1 mmoles) of benzaldehyde is added to a solution of 2.0 g. (6.6 mmoles) of 1-methyl-4-amino-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml. of benzene, and the mixture is stirred at room temperature overnight. At the end of the reaction the mixture is evaporated to dryness under reduced pressure, the residue is triturated with 20 ml. of ether, and the solid substance is filtered off. 2.1 g. (80.7 %) of 1-methyl-4-benzalamino-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are obtained. M.p.: 157°-158° C. (after recrystallization from ethanol). Rf(4) = 0.7.
Reaction SMILES: C(N[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2CN(CCC)CCC)=[CH:7][CH:6]=1)(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][CH:13]=2)[CH2:9][CH2:10]1
Reactant: CCCN(CCC)CC1CCc2ccc(NC(C)=O)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCC2

Procedure:
A solution of the free base of compound 2a (5.0 g) in dry THF (25 ml) was added dropwise to a suspension of 1 g LiAlH4 in dry 50 ml THF at 20-25° C. The mixture was refluxed for 2 hours, excess LiAlH4 was destroyed by cautiously adding 2 ml diluted aqueous NaOH solution. Inorganic salts were filtered off and the crude 6-ethylamino-1-(N,N-dipropylaminomethyl(indan was isolated as a viscous oil upon evaportion of the solvents. Yield: 3.0 g. All off the thus obtained ethylaminoindan derivative was dissolved in 60 ml dichloromethane and 2.3 ml triethylamine was added. The mixture was cooled to 0° C. and a solution of 1 ml acetylchloride in 10 ml dichloromethane was added dropwise at 5-10° C. The mixture was stirred for another hour at room temperature. Water (100 ml) was added and the organic phase was subsequently separated and worked up. The remaining oil was dissolved in acetone and oxalic acid was added. The oxalate salt of the title compound 14a crystallized and was filtered off and dried in vacuo. Yield: 2.5 g. Mp: 129-130° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]2[CH3:21])=[CH:8][CH:7]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[CH3:21][C:13]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: C1CCNC1
Reactant: Cc1cc2ccccc2n1-c1ccc(OCCCCl)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 42.8 %

Procedure:
1-[4-(3-Chloropropoxy)phenyl]-2-methyl-1H-indole (20 mg, 0.067 mmol) was dissolved in N-methylpyrrolidinone (0.5 mL), and pyrrolidine (0.017 mL, 0.2 mmol), potassium carbonate (46 mg, 0.34 mmol), and a catalytic amount of potassium iodide were added. The reaction was heated to 70° C. overnight. The reaction was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The residue was purified by semi-prep LC-MS to give 9.6 mg of the desired product (43% yield). LC-MS (C22H26N2O calc'd 334) m/z 335 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.58-7.53 (m, 1H), 7.26-7.25 (m, 3H), 7.12-6.99 (m, 4H), 6.37 (s, 1H), 4.10 (t, J=6 Hz, 2H), 2.99-2.90 (m, 6H), 2.24 (s, 3H), 2.22-2.14 (m, 2H), 2.00-1.90 (m, 6H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([I:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In nitrogen-purged flask is added 5.1 g (0.023 moles) of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine in 50 ml dry acetonitrile. Cool to 0° C. and add 5.54 g (0.025 moles) of NIS dissolved in 90 ml dry acetonitrile. Allow bath to come to room temperature and the reaction to stir overnight. Evaporate solvents, take up in ethyl acetate and wash two times with 50% aqueous solution of sodium sulfate then brine. Dry over sodium sulfate, filter and evaporate to a residue. Triturate in small amount of acetonitrile and filter solid. Repeat several times to obtain the title compound as light tan solid weighing 7.29 g (0.021 moles, 91.3%). 1H-NMR (DMSO-d6): δ 6.96 (s, 1H); 3.0-3.3 (m, 1H); 2.51 (s, 3H); 2.35 (s, 3H); 1.71-1.80 (m, 4H); 0.71 (t, J=7.48 hz, 6H) ppm. MS/ES+=344 (100%, M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[N:6]([CH2:16][CH2:17]O)[C:7](=[O:15])[NH:8]2.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:17][CH2:16][N:6]1[C:5](=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[NH:8][C:7]1=[O:15]
Reactant: COc1ccc2[nH]c(=O)n(CCO)c(=O)c2c1OC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(=O)n(CCCl)c(=O)c2c1OC

Procedure:
A mixture of 5,6-dimethoxy-3-hydroxyethylquinazolin-2,4-dione (2.0 g, 7.51 mM) and thionyl chloride (0.76 ml, 10.45 mM) in CHCl3 (20 ml) was heated at reflux for 4 hours under nitrogen with vigorous mechanical stirring. Trituration of the solid reaction mixture followed by drying afforded crude product as an off-white solid. The crude product was recrystallized from MeOH (100 ml) and dried to afford the title compound as a white solid; 0.86; (A); mp 118°-120° C.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=2)[CH:16]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[C:18]([C:20]([NH:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:9])=[O:21])[N:19]=2)[CH:16]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Cc1ccccc1CN
Product: Cc1ccccc1CNC(=O)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using o-tolylmethanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC[C@@H](N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:45][CH2:46][N:48]([CH3:47])[CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN1CC[C@@H](N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methyl-3-(R)-amino pyrrolidine dihydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.90 (m, 12H) 2.18 (m, 1H) 2.26 (s, 3H) 2.32-2.56 (m, 2H) 2.60-2.68 (m, 2H) 3.34 (s, 3H) 3.95 (s, 3H) 4.07 (t, J=13.52 Hz, 2H) 4.34-4.54 (m, 2H) 7.51 (d, J=8.0 Hz, 1H), 7.54 (br. s., 1H) 7.90 (s, 1H), 8.21 (s, 1H) 8.27 (d, J=8.0 Hz, 1H) 8.40 (br. s., 1H). Melting point: 98-99° C. [M+H] calculated for C27H35F2N7O3, 544. found 544.