Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:31]3[N:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]3=[N:29][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12][CH2:13][CH2:14]3)=[CH:9][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(N)nn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 78 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (0.67 g, 1.50 mmol), 3-amino-6-methoxypyridazine (CAS Registry No. 7252-84-8, 0.23 g, 1.80 mmol, 1.2 eq), N,N-diisopropylethylamine (0.74 mL, 1.50 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10 g) in isopropanol (78 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure to give tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.55 g, 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:39]=[CH:40][N:41]=3)[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]([NH:25][C:26]4[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:24])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(N3CCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2cc(N3CCC(C(=O)Nc4ccc(C(=O)O)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.3 %

Procedure:
A mixture of tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxamido)benzoate (200 mg, 0.36 mmol) and TFA (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 2 h. The residue was concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 25% acetonitrile/75% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidine-3-carboxamido)benzoic acid (6 mg, 4%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.54 (s, 1H), 8.88 (brs, 2H), 7.95-7.82 (m, 4 h), 7.49-6.69 (m, 3H), 4.06-3.57 (m, 6H), 3.19-3.02 (m, 5H), 2.05 (brs, 2H). LC-MS: [M+H]+, 504, tR=1.269 min, HPLC: 96.47% at 214 nm, 97.69% at 254 nm, tR=4.72 min.
Reaction SMILES: I[As:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:19])([F:18])I>>[C:3]1([As:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([F:19])([F:18])[F:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)I
Reactant: I[As](c1ccccc1)c1ccccc1
Product: FC(F)(F)[As](c1ccccc1)c1ccccc1

Procedure:
R. Cullen in an article "Perfluoroalkyl Arsenicals, Part II The Preparation and Properties of Aryl Perfluoroalkyl Arsenicals", reported in Canadian Journal of Chemistry, Volume 38, 1960, pg. 445-451, describes the reaction of iododiphenylarsine with trifluoroiodomethane to produce diphenyltrifluoromethylarsine. Thermal decomposition of diphenyltrifluoromethylarsine resulted in undisclosed black solid deposit.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[CH2:7][CH2:8][N:9]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CC(=O)NCCC2=CCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CC2=NCCC3=C2CCCC3)cc1
Yield: 105.7 %

Procedure:
27.3 g (0.1 mol) of N-[2-(cyclohexen-1-yl)ethyl]-p-methoxyphenylacetamide and 91.4 g (0.596 mol) of phosphorus oxychloride in 230 ml of toluene were heated to 100° C. under argon for 30 min. The mixture was then evaporated in a rotary evaporator, and the residue (46 g) was washed twice with 70 ml of petroleum ether and then dissolved in 270 ml of dichloromethane. The solution was added to 270 ml of a 12% strength aqueous ammonia solution at 0° C. with vigorous stirring. The organic phase was washed with 90 ml of water, dried over sodium sulfate and evaporated, giving 27.0 g of a viscous yellow-brown oil, which was used immediately for the hydrogenation.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH2:13][CH2:12]3)(=O)=O.[NH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>>[CH3:19][C:17]1[CH:18]=[C:9]2[CH2:8][CH:7]([CH2:6][NH:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[O:21][C:10]2=[C:11]2[C:16]=1[NH:15][C:14](=[O:20])[CH2:13][CH2:12]2
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(COS(C)(=O)=O)C2
Reactant: NCc1cccs1
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNCc1cccs1)C2
Temperature: 150 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A mixture of 2-methanesulfonyloxymethyl-5-methyl-2,3,6,7,8,9-hexahydrofuro-[2,3-f]quinoline-7-one (1350 g) and 2-aminomethylthiophene (7.06 g) was stirred in a hot bath (150° C.) for 1 hour in the stream of argon. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform The obtained solution was washed with sodium bicarbonate water and water, then dried. When crystallized from ethanol, 0.790 g of a free base of the title compound was obtained in pale yellow prisms (mp.: 151°-153° C., yield: 55.5%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH2:29])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: CN1CCC(CN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc4ncnc(N)c4n3)c2)CC1

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with (1-methyl-4-piperidyl)methanamine (CAS 7149-42-0) (77 mg, 0.6 mmol), HATU (129 mg, 0.33 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-((1-methylpiperidin-4-yl)methyl)benzamide 22. LC/MS (ESI+): m/z 377 (M+H). 1H NMR (400 MHz, DMSO) δ 8.48 (d, J=8.8 Hz, 2H), 8.42 (s, 2H), 8.23 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 7.96 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.45 (d, J=6.9 Hz, 1H), 2.90 (s, 2H), 2.73 (d, J=52.3 Hz, 4H), 2.19 (s, 1H), 2.04 (s, 3H), 1.83 (s, 2H), 1.64 (s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12](I)[C:11]([OH:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17]>>[CH2:1]([C:8]1[N:13]=[C:12]2[CH:17]=[C:16]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]4)=[CH:20][C:19]=3[F:33])[O:15][C:11]2=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cc2ccccc2)nc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Product: COC(=O)C1CN(Cc2ccc(-c3cc4nc(Cc5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3 and general procedure G from 6-benzyl-2-iodopyridin-3-ol (0.500 g, 1.61 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.477 g, 1.93 mmol). 1H NMR (300 MHz, CDCl3) δ ppm 7.93 (t, J=7.9 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 7.37 (d, J=3.1 Hz, 1H), 7.10-7.33 (m, 7H), 7.04 (d, J=8.5 Hz, 1H), 4.27 (s, 2H), 3.72 (s, 3H), 3.65 (s, 2H), 3.48-3.60 (m, 2H), 3.30-3.40 (m, 3H). MS (ESI) m/z: Calculated; 430.2 Observed: 431.1 (M++1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:25][CH2:26][CH2:27][CH3:28].[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH2:25][CH2:26][CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 113 h
Yield: 11 %

Procedure:
Triethylamine (0.031 mL, 0.23 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (67 mg, 0.23 mmol) in dichloromethane (45 mL). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 mL, 0.23 mmol) was added. The reaction mixture was removed from the ice bath. The reaction mixture was allowed to stir at ambient temperature for ˜113 hours. Analysis by HPLC indicated that the reaction was not complete. The dichloromethane was removed under reduced pressure. 1,2-Dichloroethane (50 mL) was added and the reaction mixture was heated to 60° C. After 3 hours, more dimethylsulfamoyl chloride (2.5 μL) was added and heating was continued. After 22 hours the reaction temperature was raised to reflux and the reaction mixture was refluxed for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate to provide 10 mg of N′-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamide as an off-white crystalline solid, m.p. 129.5-131° C. M/Z=397.1 (M+H)+.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([OH:12])[CH2:9][CH2:10][OH:11].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>[Cl-].[Na+].O>[Cl:13][C:14]1[N:19]=[C:18]([O:11][CH2:10][CH2:9][CH2:8][OH:12])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCOc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 14.7 %

Procedure:
To a round-bottom flask charged with NaH (336 mg, 8.29 mmol, 60% dispersion in mineral oil) and THF (100 mL), 1,3-propanediol (0.91 mL, 12.6 mmol) was added dropwise [H2 evolution] at rt. The reaction mixture was stirred for 30 min, then 2,4-dichloropyrimidine (5.0 g, 33.6 mmol) was added, and the reaction mixture was stirred for an additional 72 h. Brine was slowly added and the aqueous phase was extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to provide the product (350 mg, 22%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.01 (qt, 2H), 2.43-2.52 (b, 1H), 3.76 (t, 2H), 4.51 (t, 2H), 6.63 (d, 1H), 8.25 (d, 1H) LC-MS: RT=1.05 min, (M+H)+ 189.1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([N:35]([CH2:38][C:39](O)=[O:40])[CH2:36][CH3:37])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:39](=[O:40])[CH2:38][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCN(CC)CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and N,N-diethylaminoacetic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-2-diethylamino-ethanone. MS (M+H)+: 459.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=[S:28])[CH2:24][C:25](=O)[CH3:26])=[O:4].[C:29]([O:33][C:34]([N:36]([CH3:38])[NH2:37])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23](=[S:28])[CH2:24][C:25](=[N:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH3:38])[CH3:26])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: CN(N)C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=NN(C)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with N-methyl-hydrazinecarboxylic acid tert-butyl ester (CAS Reg. No. 21075-83-2) to give the title compound as off-white solid. MS (ESI): m/z=566.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C@H:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12].F[C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1>COCCOC>[CH3:7][C@H:8]([O:13][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[C@H](C)O
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
Sodium t-butoxide (4.86 g, 50.6 mmol) was added portionwise to a stirred mixture of (S)-2-hexanol (12 g, 117 mmol) and 1,2-dimethoxyethane (12 ml). The resultant mixture was heated to 50° C. under an atmosphere of nitrogen and then 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (3 g, 12.65 mmol) was added. The resultant mixture was maintained at 50° C. for 20 hours when LCMS indicated complete reaction. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was washed with water (100 ml) then saturated brine (50 ml), dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (100 g) eluting with a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.665 g).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1>CCCCCC.C(OCC)C>[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][CH:9]=2)([OH:19])[CH2:15][CH2:14]1
Reactant: Cn1cccc1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN1CCC(O)(c2cccn2C)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A 1.6 M solution of n-butyllithium in hexane (175 ml) was added dropwise at room temperature to a solution of 24.2 g of N-methylpyrrole in 250 ml of diethyl ether contained in a reaction flask (under a nitrogen blanket). After addition was completed, the resulting mixture was heated at reflux with stirring for 16 hours, then cooled to 0° C. 34 Grams of 1-methyl-4-piperidone was added dropwise from a dropping funnel with the temperature maintained at 0° C. during the addition by cooling the reaction flask with dry ice-acetone bath. The reaction mixture was stirred at room temperature for 3 hours, and then quenched in ice water to yield 26 g of the title compound in a crystalline form; recrystallization from heptane gave white prisms, m.p. 123°-123.5°.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (27, 2.45 g, 8.77 mmol) in 68 mL of tetrahydrofuran, sodium hydride (0.4208 g, 10.52 mmol) is added and the reaction is stirred at room temperature for 30 minutes. 4-Methyl-benzenesulfonyl chloride (28, 1.838 g, 9.643 mmol) is added and the reaction stirred at room temperature overnight. Water is added and the reaction is extracted with ethyl acetate, resulting in some precipitate that is removed by filtration. The aqueous layer is separated and extracted with ethyl acetate. The organic layers are combined, washed with water, then brine and dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The residue is suspended in ethyl acetate, sonicated for 30 minutes, and the solid collected by filtration to provide the desired compound (29, 3.325 g). MS (ESI) [M+H+]+=433.8.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH2:26])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
Propionyl chloride (2.02 mL, 23.1 mmol) and DIPEA (14.4 mL, 84.0 mL) were added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) in CH2Cl2 (195 mL). The mixture was stirred for 15 min at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl (2×), with aq. 1M NaOH (1×) and with brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→3:2) yielded the title compound (5.08 g, 71%). LC-MS: tR=1.09 min; ES+: 383.41.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].O>CCO>[CH3:11][N:12]([CH3:13])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CCO
Product: CN(C)c1ncccc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (1.00 g, 0.00631 mol) in absolute EtOH (17 ml), under nitrogen, was treated, dropwise during 10 minutes, with 3.86 g (0.0214 mol) of 25% aqueous dimethylamine and kept at ambient temperature (25° C.) for 30 minutes. The mixture was mixed with water and extracted with EtOAc. The extract was washed with water, dried (MgSO4) and concentrated to give 1.05 g of the titled product, a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][CH:12]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([NH:21][CH2:20][CH2:19][NH2:22])=[N:13][CH:12]=1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)c(N)c1
Reactant: NCCN
Product: Cc1ccc(NC(=O)c2ccc(NCCN)nc2)c(N)c1
Yield: 51 %

Procedure:
N-(2-Amino-4-methyl-phenyl)-6-chloronicotinamide (261 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (145 mg, 51% yield) as a brown solid. LC-MS (m/z) 286 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[CH2:19]C1C=CC(C(O)=O)=CC=1.COC(=O)C1C=CC(CCl)=CC=1.CN1CCNCC1>>[CH3:19][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([CH2:8][N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:10][CH:11]=1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: CN1CCNCC1
Agent: COC(=O)c1ccc(CCl)cc1
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1

Procedure:
4-(4-methylpiperazin-1-ylmethyl)benzoic acid (17) is obtained as described in the following Scheme 5. 4-Chloromethylbenzoic acid (14) is first esterified to a methyl ester to protect an acid group in the following reaction. 4-Chloromethyl-benzoic acid methyl ester (15) is then allowed to react with 1-methylpiperazine to give 4-(4-methylpiperazin-1-ylmethyl)benzoic acid methyl ester (16). Methyl ester is cleaved by heating with potassium hydroxide in methanol. 4-(4-methylpiperazin-1-ylmethyl)benzoic acid is reacted as described above in Scheme 4 with aminopyridine derivatives (3) to result in N-4-(4-methylpiperazin-1-ylmethyl)benzamide derivatives of (13). By a similar manner other N-4-(piperazin-1-ylmethyl)benzamide derivatives of (13) can be prepared.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=1)=[CH:12][C:11]2=[O:34])=[O:5])C.C1COCC1.[OH-].[Li+].Cl>CO>[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[O:14][C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=1)=[CH:12][C:11]2=[O:34])([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2c(=O)cc(-c3ccc(OCc4ccc5ccccc5n4)cc3)oc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
8-Ethoxycarbonyl-4'-(2-quinolinylmethoxy)flavone was dissolved in a mixed solvent of methanol:THF:5% aqueous solution of lithium hydroxide (1:1:1 V/V), followed by stirring at room temperature for 2 days. The reaction mixture was acidified with 3 N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and methanol, and then recrystallized from DMF, whereby the title compound represented by the following formula was obtained (yield: 89%). ##STR31##