Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Li]CCCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:32])([F:31])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[O:22])=[N:18][CH:19]=1>CCOCC>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:31])([F:32])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])([C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[OH:22])=[N:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1cncnc1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Br)cn1
Reaction time: 1 h
Yield: 13.2 %

Procedure:
To a stirred solution of 5-bromopyrimidine (0.45 g, 2.87 mmol) in Et2O (30 mL) was added n-BuLi (1.6 M in hexane; 1.8 mL, 2.87 mmol) at −78° C., and the mixture was stirred for 1 h under inert atmosphere. A solution of compound E (1.0 g, 2.87 mmol) in Et2O (10 mL) was added to the reaction mixture at −78° C., and stirring was continued for another 1 h. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4Cl solution (20 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40% EtOAc/hexanes) afforded 58 (0.16 g, 0.38 mmol, 13.3%) as a light yellow solid. 1H NMR (500 MHz, CDCl3): δ 9.10 (s, 1H), 8.80 (s, 2H), 8.55 (s, 1H), 8.06 (dd, J=8.5, 1.5 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.71-7.67 (m, 1H), 7.00 (br s, OH), 6.88-6.86 (m, 1H), 6.74-6.70 (m, 1H). MS (ESI): m/z 429 [M+H]+. HPLC: 98%.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][C:7]([CH:8]=[N:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[N:9][N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(C=NNC(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1
Temperature: 45 °C
Yield: 89.3 %

Procedure:
To a solution of 4-methoxy-benzoic acid (4-diethylamino-benzylidene)-hydrazide (1) (0.28 g, 0.00086 mol) in DMF (10 ml), was added α-bromo-p-xylene (0.48 g, 0.0026 mol) and powdered K2CO3 (0.83 g, 0.006 mol) and the resulting mixture heated at 45° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were concentrated to an oil, which was purified by flash chromatography (gradient elution, 9:1 to 7:3 Hexanes/EtOAc to give the desired product as oil 0.33 g in 88% yield. 1H NMR (CDCl3) δ 7.91 (d, 2H), 7.63 (s, 1H), 7.30 (d, 2H), 7.20 (d, 2H), 7.14 (d, 2H), 6.97 (d, 2H), 6.57 (d, 2H), 5.38 (s, 2H), 3.90 (s, 3H), 3.37 (q, 4H), 2.32 (s, 3H), 1.16 (t, 6H). 13C NMR (CDCl3) δ 167.3, 158.3, 145.8, 137.9, 133.8, 129.9, 126.7, 125.8, 124.2, 118.9, 111.2, 109.8, 108.3, 52.5, 42.5, 41.5, 18.2, 9.6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[NH2:13][C:14]1[CH:19]=[C:18](Cl)[C:17]([C:21]#[N:22])=[CH:16][N:15]=1>CS(C)=O>[NH2:13][C:14]1[CH:19]=[C:18]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:17]([C:21]#[N:22])=[CH:16][N:15]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: N#Cc1cnc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cnc(N)cc1Oc1ccc2[nH]ccc2c1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
5-Hydroxyindole (313 mg, 2.35 mmol) was dissolved in dimethyl sulfoxide (3 ml); and sodium hydride (90 mg, 2.25 mmol) was gradually added thereto while stirring at room temperature. After the reaction mixture was stirred for 1 hour, 2-amino-4-chloro-5-cyanopyridine (300 mg, 1.96 mmol) synthesized in Production example 215-3 was added thereto; and the reaction mixture was heated and stirred at 120° C. for 4 hours. After allowing to be cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off; the residue was subjected to silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol); fractions containing the desired compound was concentrated under reduced pressure; ether was added thereto; and the solid was filtered off, and dried under reduced pressure to yield the title compound (95 mg, 0.38 mmol, 59%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:33][CH2:34][CH2:35][CH3:36])[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH2:35][CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CCCNCC
Product: CCCN(CC)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and ethyl(propyl)amine were processed as described in Example 1D to provide the titled compound. 1HNMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.2-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m, 2H), 1.38 (t, J=7.5 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][CH3:32])[CH2:28][CH2:29]3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CCCN1CCN(CCCCl)CC1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCN(CCCOc2ccc3nc(C#N)nc(NCC(C)(C)C)c3c2)CC1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31 mmol), 1-(3-chloro-propyl)-4-propyl-piperazine (0.62 mmol) and cesium carbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 102-104° C., Rf=0.4 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1.C(#N)C.[C:28]([C:36]1[CH:46]=[CH:45][C:39]([O:40][CH2:41][C:42](Cl)=[O:43])=[CH:38][CH:37]=1)([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[CH:46][C:36]([C:28]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:29])[CH3:30])=[CH:37][CH:38]=3)[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1
Reactant: Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Reactant: CC(C)(C)CC(C)(C)c1ccc(OCC(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)CC(C)(C)c1ccc(OCC(=O)Nc2ccc(Cl)c(Nc3cc(=O)n(-c4c(Cl)cc(Cl)cc4Cl)[nH]3)c2)cc1
Yield: 854.2 %

Procedure:
Forty point four grams of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-aminoanilino)-5-pyrazolone were dissolved into 250 ml of acetonitrile, and to the solution were added 9.4 grams of pyridine. To this mixture, while being refluxed by heating, were dropwise added 28.3 g of 4-t-octylphenoxyacetyl chloride, and the reflux was further continued for another hour. The acetonitrile was distilled off from the reaction liquid under reduced pressure, then 500 ml of water and ethyl acetate were added to the liquid, and then the reaction product was extracted by ethyl acetate. The residuum that has been obtained by distilling off the ethyl acetate phase under reduced pressure was recrystallized from 300 ml of ethanol, whereby 55 g of objective 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-(4-t-octylphenoxyacetamido)anilino]-5-pyrazolone were obtained. Melting point: 126° to 128° C. The structure was confirmed through the procedures of NMR, IR and MASS.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[C:4](=[O:11])O1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(N(CC)C(C)C)(C)C>[CH2:13]([NH:17][C:4](=[O:11])[C:5]([CH3:9])([CH3:10])[C:6]([OH:7])=[O:8])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: CC1(C)OC(=O)C(C)(C)C(=O)O1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)C(C)(C)C(=O)O
Yield: 60 %

Procedure:
1.72 g (10 mmol) —2,2,5,5-Tetramethyl-[1,3]dioxane-4,6-dione and 1.02 ml butylamine were stirred in 7 ml N,N-diisopropyl-ethylamine for 18 hours at room temperature. The excess N,N-diisopropyl-ethylamine was decanted and the residue was extracted with 1N aqueous hydrochloric acid/ethylacetate. The ethylacetate phase was washed with 1N aqueous hydrochloric acid, brine and was dried over sodiumsulfate. Evaporation of the solvent and recrystallisation from dichloromethane/heptane yielded 60% N-butyl-2,2-dimethyl-malonamic acid as white solid, MS m/e (%): 188.4 (M+H+, 100).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CN(C)[CH:32]=[O:33]>O1CCCC1.CCCCCC>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][C:23]=1[CH:32]=[O:33]
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
A solution of 68 ml (0.4 mol) of 2,2,6,6-tetramethyl- piperidine in 1 l of tetrahydrofuran is cooled under argon to -10° and at this temperature there are added dropwise thereto while stirring 250 ml of a 1.6M solution of n-butyllithium in hexane. Subsequently, 62 ml (0.4 mol) of 1,3-bis(trifluoromethyl)-benzene are added dropwise thereto at -10° within 5 minutes. The resulting wine-red solution is stirred at -10° for a further 5 minutes and then 62 ml (0.8 mol) of N,N-dimethylformamide are allowed to flow in rapidly. The internal temperature rises by 15° as a consequence of the exothermic reaction. The dark brown solution obtained is then added slowly and under a slight argon pressure to 1.2 l of stirred, ice-cold 1M hydrochloric acid. The internal temperature rises to 10° as a consequence of the stongly exothermic reaction in spite of constant cooling. The resulting emulsion is diluted with 750 ml of hexane, the aqueous phase (1.5 l) is separated and stored for the recovery of 2,2,6,6-tetra- methylpiperidine. The organic phase (1.9 l) is extracted twice with 1 l of water each time, dried over sodium sulphate, filtered and the organic solvent is distilled off at 40° under a vacuum (20 kPa). The residue (about 100 ml) is distilled over a column having a length of 20 cm, firstly at 50° bath temperature under a vacuum of 20 kPa in order to remove the residual solvent, then the bath temperature is increased to 80° and the vacuum is increased to 1.4 kPa. A forerun is removed until the constant internal temperature of 57° has been reached and then the residue distils over as a fraction at 57°/1.4 kPa. There are obtained 68 g (70%) of 2,4-bis(trifluoromethyl)benzaldehyde with a purity (GC) of 96-98%.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][C:12](=[O:33])[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:35])([CH3:34])[O:3]1.Cl.CCOC(C)=O>>[NH2:25][C@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:35])([CH3:34])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2cc(NC(=O)[C@H](N)Cc3ccc(C(F)(F)F)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
(R)-tert-butyl 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-ylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (CLXII) (1.00 g, 2.1 mmol) was treated with HCl/EtOAc (4.2 M, 15 mL) and was stirred for 30 minutes at room temperature. The solvent was removed under vacuum, and the residue was triturated with hexane to give the hydrochloride salt of (R)-2-amino-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-3-(4-(trifluoromethyl)phenyl)propanamide (CLXIII) as a white solid (0.86 g, 2.01 mmol, 94% yield). 1H NMR (DMSO-d6) δ ppm 1.39 (s, 6H), 3.19 (dd, J=13 Hz, J=13 Hz, 1H), 3.29-3.32 (m, 1H), 4.33-4.40 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.55 (d, J=7 Hz, 2H), 7.60 (d, J=8 Hz, 1H), 7.66 (d, J=7 Hz, 2H), 7.86 (s, 1H), 8.45 (brs, 3H), 9.1 (s, 1H), 11.03 (s, 1H); 19F NMR (DMSO-d6) δ ppm −60.25 (s, 3F). ESIMS found for C19H20BF3N2O3 m/z 393.4 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Br[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:17][C:16]1[C:11]([N:1]2[CH2:2][CH:3]=[C:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1Br
Reactant: O=C(O)C1=CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Temperature: 90 °C

Procedure:
1,2,3,6-Tetrahydro-4-pyridinecarboxylic acid (7.0 g, 47 mmol) and 2-bromo-3-chloropyridine (11.0 g, 57 mmol) were combined in DMSO (100 mL) and treated with anhydrous K2CO3 (8.0 g, 58 mmol). The mixture was heated at 90° C. overnight, allowed to cool to room temperature, and then concentrated under reduced pressure. The residue in dichloromethane (200 mL) was cooled to −78° C. and treated with an excess of TFA (10 mL, 130 mmol) dropwise. The mixture was allowed to warm to room temperature and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>>[NH2:19][C:18]1[O:4][C:5]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:8])[C:17]=1[C:16]#[N:20]
Reactant: N#CCC#N
Reactant: COc1cccc(C(=O)Cl)c1OC(C)=O
Product: COc1cccc2c(=O)c(C#N)c(N)oc12

Procedure:
In the same way as described in Example 3, 2-acetoxy-3-methoxy-benzoyl chloride and malononitrile are reacted to give a crystalline product, mp 300° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[NH:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH2:63][CH3:64])[CH:52]=1)=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[NH:58][C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH2:63][CH3:64])[CH:52]=1)=[O:50]
Reactant: CCOc1cc(C(=O)OC)c2nc(N)[nH]c2c1F
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)c2[nH]c(NC(=O)c3cc4ccccc4cn3)nc2c1F
Yield: 44 %

Procedure:
0.3 g (1.5 mmol) of isoquinoline-3-carboxylic acid and 0.6 g (1.6 mmol) of HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.25 g (1.0 mmol) of 2-amino-6-ethoxy-7-fluoro-1H benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A to produce 0.18 g (0.44 mmol, 44%) of 6-ethoxy-7-fluoro-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 409 (M+1)+.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:5]2)[O:3]C1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH2:11]([NH:10][CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)[CH2:12][CH3:13]
Reactant: CCCNC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCNC1CCC(=O)CC1
Temperature: 5 °C
Reaction time: 24 h

Procedure:
4-N-propylamino-cyclohexanone-ethyleneketal 2 (134 g, 0.673 mol) was taken in tetrahydrofuran (268 ml) and cooled to 4-6° C. Concentrated hydrochloric acid (178 ml, 2.01 mol) was diluted with water (2144 ml) and the mixture was cooled to 4° C. This diluted hydrochloric acid was added to the reaction mixture at 4-6° C. in 15 minutes. The reaction was allowed to come to 24-26° C. and stirring was continued for 24 hours. The reaction mass (2750 ml) was concentrated to 1800 ml at 50° C. and 35 mbar pressure. Sodium carbonate (148 g, 1.4 mol) was added to achieve pH 10. The reaction mixture was extracted with dichloromethane (3670 ml). The dichloromethane layers were combined and dried over sodium sulfate (20 g). The dichloromethane layer was concentrated to dryness at 40° C. and 15 mbar pressure. The product 3 was yellow viscous oil. The weight of the product 3 obtained was 52.5 g (52.84%); GC purity 86.07%.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:28][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:14])[CH:9]=2)[NH:4][CH:3]1[C:15]1[CH:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH:18]=[C:17]([CH3:27])[CH:16]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc(N2CCOCC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)cc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 39.8 %

Procedure:
A mixture of 3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.39 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (110 mg, 0.59 mmol), 4-dimethylaminopyridine (72 mg, 0.59 mmol), methane sulfonamide (110 mg, 1.17 mmol) in dichloromethane (5 mL) was heated for at 65° C. for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[3,3-dimethyl-2-(3-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (71 mg, 40%) as a light yellow solid: LC/MS m/e calcd for C24H31N3O4S (M+H)+: 458.6, observed: 458.2.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>CO.CCOCC>[OH:13][N:12]=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(C=NO)cc1
Temperature: 70 °C
Yield: 89 %

Procedure:
The compound was prepared according to Biasotti et al. Bioorg. Med. Chem. 2003, 11, 2247. A suspension of 4-formylbenzonitrile (500 mg, 3.81 mmol, 1.00 eq), hydroxylamine hydrochloride (290 mg, 4.19 mmol, 1.10 eq), and sodium acetate (1.56 g, 19.05 mmol, 5.00 eq) in MeOH (50 mL) was heated at 70° C. for 4 h before concentration to dryness. The residue was then slurried in Et2O, filtered, and concentrated to afford the desired intermediate (496 mg, 3.39 mmol, 89%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C.[Pt]>[NH2:7][C:5]1[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]([CH3:1])[CH:6]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)c1cc(N)cn1C
Reaction time: 16 h

Procedure:
Ethyl 1-methyl-4-nitro-2-pyrrolecarboxylate (16.0 g, 0,081 mol) (M. J. Weiss, J. S. Webb and J. M. Smith, J. Amer. Chem. Soc., 79, 1266 (1957)) is dissolved in (200 mL) ethanol and (1.60 g) of 10% platinum on carbon is then added. The mixture is shaken for 16 hours in a PARR hydrogenator. The catalyst is removed by filtration through a pad of celite and the filtrate is concentrated in vacuo to a yellow oil. The oil is carried on directly without purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:13]([CH:15]([CH2:19][CH3:20])[C:16](Cl)=[O:17])[CH3:14].[Li+].[OH-].O>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:16](=[O:17])[CH:15]([CH2:19][CH3:20])[CH2:13][CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CCC(CC)C(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reaction time: 7 h
Yield: 82.4 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in pyridine at 0° C. was treated dropwise with 2-ethylbutanoyl chloride (176 mg, 1.30 mmol). After 7 hours, 2M LiOH (5 mL) was added to the mixture and stirring was continued at room temperature for 30 minutes. Water (25 mL) was then added, and the solid formed was filtered, washed with water (3×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide (235 mg, 82% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.06 (s, 1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.53 (s, 1H), 2.30-2.24 (m, 1H), 1.62-1.52 (m, 2H), 1.47-1.41 (m, 2H), 0.90 (t, 6H); LCMS (APCI+) m/z 328, 330 (M+H)+, Retention time=3.20 minutes (Method 2).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12]Br)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].C1COCC1.[OH-].[NH4+:20]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]2[C:3]=1[CH2:12][NH:20][C:5]2=[O:6]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCc2c(Br)cccc21
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (27 mmol) in THF (100 mmol) was added ammonium hydroxide (9 mL) dropwise at rt. The reaction mixture was allowed to stir overnight and then diluted with 30 mL of water. The solution was extracted with DCM, dried over Na2SO4, filtered and concentrated to give 4-bromoisoindolin-1-one (5.20 g, 91%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>CC(O)=O>[C:1]([NH:4][C:5]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
The product obtained in Step 3 (6.0 g, 33.9 mmol) was dissolved in AcOH (100 mL), then HNO3 (1.9 mL, 47.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then poured into ice-water. The water layer was extracted with ethyl acetate. The organic layer was dried, concentrated, purified by column chromatography to obtain a product (7.0 g, 93.3%).