Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][OH:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:22]([Cl:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[ClH:41].[C:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][OH:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(=NO)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: Cl
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
A mixture of 43.2 g of the product of Step A in 120 ml of dry dimethylformamide was cooled to -35° C. and after the addition of 32 ml of triethylamine, 60 g of trityl chloride were added thereto in fractions over 30 minutes. The temperature was allowed to increase during which total dissolution occurred and the mixture was heated at 30° C. for one hour and was then poured into 1.2 liters of ice water containing 40 ml of 22° Be hydrochloric acid. The mixture was stirred in an ice bath and was then vacuum filtered. The recovered product was rinsed with N hydrochloric acid and was empasted with ether to obtain 69.3 g of the syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetate HCl.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reaction time: 2 h

Procedure:
Alternative preparation: To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (495.4 mg, 1.610 mmol, 1 eq), 1-piperidinepropanoic acid (335.4 mg, 2.133 mmol, 1.3 eq), and TBTU (624.4 mg, 1.945 mmol, 1.2 eq) in anhydrous DMF (15 mL), DiPEA (1.4 mL, 8 mmol, 5 eq) was added at rt, under N2, and stirred for 2 h. The solvent was evaporated under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with MeOH:DCM 2%→5%→10%→7N NH3/MeOH:DCM 2%→5%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]([OH:20])([C:6]#[C:7][CH2:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:4][CH3:5])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[O:38]1[CH:43]=[CH:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[CH2:1]([C:3]([O:20][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][O:38]1)([CH2:4][CH3:5])[C:6]#[C:7][CH2:8][O:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCC(O)(C#CCOS(=O)(=O)c1ccc(C)cc1)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(C#CCOS(=O)(=O)c1ccc(C)cc1)(CC)OC1CCCCO1
Yield: 85.1 %

Procedure:
A solution of Compound 401 (6.5 g), PPTS (0.73 g) and 3,4-dihydro-2H-pyran (2 g) in dichloromethane (33 ml) was stirred at r.t. for 17 h. Dichloromethane (250 ml) was added and the solution was washed with brine (250 ml). Work-up with chromatography with ether/pentane 1:1 (v/v) gave the title compound (7.1 g). 1H NMR: 0.85 (t, 6H), 1.55 (q, 4H), 1.42-1.90 (m, 6H), 2.45 (s, 3H), 3.47 (m, 1H), 3.89 (m, 1H), 4.79 (s, 2H), 4.85 (m, 1H), 7.35 (d, 2H), 7.82 (d, 2H) .
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:30]#[C:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)#[N:30]
Reactant: N#CBr
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C#N)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (39 mg, 0.10 mmol), Cyanogen Bromide (13 mg, 0.12 mmol) and Potassium Carbonate (28 mg, 0.20 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC to give N-(5-(4-cyanopiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 176. MS m/z 413.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.39 (d, 1 Hz), 7.96 (s, 1H), 7.89 (d, 1H), 7.68 (d, 2H), 7.58 (s, 1H), 7.50 (d, 1H), 7.46 (d, 2H), 7.37 (dd, 1H), 3.74 (s, 2H), 3.35 (t, 4H), 3.18 (t, 4H), 2.55 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[NH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(N)CO
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(CO)Nc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (20.0 g, 109 mmol) in acetonitrile (500 mL) was added triethylamine (11.03 g, 109 mmol) at 0° C. After 5 min at room temperature, 2-amino-2-methylpropan-1-ol (9.72 g, 109 mmol) was added portionwise. The reaction mixture was stirred for another 1 h at room temperature, filtered and concentrated. Purification via silica gel column (ethyl acetate/petroleum ether=1/10 to 1/1) afforded the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([Cl:9])[O:6][CH2:7][CH3:8])[CH3:2].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[Cl-:9].[CH2:7]([O:6][CH:5]([P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:10])[CH3:8]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-chloro-2-ethoxyacetic acid ethyl ester (10 g, 60 mmol) in chloroform (30 mL) was added triphenylphosphine (15.7 g, 60 mmol) and stirred overnight at room temperature. The solvent was removed in vacuo, and diethyl ether was added. The solvent was again removed and dried on high vacuum to give (1,2-diethoxy-2-oxoethyl)triphenylphosphonium chloride (21 g, 82% yield) (679) as a foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[N:13]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)[Cl:18].[OH-].[Na+]>Cl.O>[ClH:18].[F:12][C:4]1[CH:3]=[C:2]([NH:1][NH2:13])[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(S(N)(=O)=O)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)c(F)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 4-Amino-2-fluoro-benzenesulfonamide (15.2 g, 80 mmol) in concentrated hydrochloric acid solution (180 ml) was slowly added NaNO2 (5.8 g, 84 mmol) in water (180 ml), while maintaining the internal temperature between −15° C. and −20° C. in a dry ice/acetonitrile bath. After the reaction mixture was stirred at −20° C. for 30 minutes, a solution of tin chloride (SnCl2) hydrate (90.3 g, 400 mmol) in concentrated hydrochloric acid solution (100 ml) was added dropwise, and the reaction mixture temperature was maintained between −50° C. and −10° C. with an ice/methanol bath. The stirring was continued at −10° C. for 1 hour and then at room temperature for 4 hours. The pH of the solution was adjusted to 8 by addition of 5 N NaOH solution at 0° C., and the precipitate was removed by filtration through celite. The aqueous layer was extracted with THF (3×600 ml), and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in 10% methanolic HCl solution, followed by stirring at room temperature for 1 hour. The title compound was collected by filtration (12.5 g, 65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[C:26]([O:27][CH3:28])=[CH:25][C:24]([C:29]([O:31]C)=O)=[N:23][N:22]4[C:33]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:40]>CO.C1COCC1>[C:29]([C:24]1[CH:25]=[C:26]([O:27][CH3:28])[C:21]2[N:22]([C:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:9]4([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10]4)=[CH:14][CH:15]=3)[N:20]=2)[N:23]=1)(=[O:31])[NH2:40]
Reactant: COC(=O)c1cc(OC)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(N)=O)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Yield: 63 %

Procedure:
A mixture of methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-8-methoxy-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Intermediate Example Int-9 (0.20 g, 0.38 mmol) in a solution of ammonia in MeOH (7 N, 15 mL) and THF (1 mL) was irradiated in a microwave apparatus at 130° C. for 90 min. The solids were collected by filtration to give tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 63%):
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:5]#[CH:6].Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>CN(C=O)C.CCOC(C)=O>[CH2:3]([C:7]([C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:5]#[CH:6]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: C#CCCC(C(=O)OCC)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCCC(C(=O)OCC)(C(=O)OC(C)(C)C)c1ncc([N+](=O)[O-])cn1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of NaH (60%, 2.5 g, 62.4 mmol) in 100 mL of DMF was added tert-butyl ethyl but-3-yn-1-ylpropanedioate (15 g, 62.4 mmol) drop-wise at 25° C. The mixture was stirred at 40° C. for 30 minutes and 2-chloro-5-nitropyrimidine (10.0 g, 62.4 mmol) in 50 mL of DMF was added dropwise. The resulting suspension was stirred at 50° C. for 2 hours and diluted with 500 mL of EtOAc. The mixture was washed with water (3×100 mL), brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (Petroleum ether:EtOAc=10:1) to afford the title compound; MS m/z 364 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][OH:1]
Reactant: NCc1ccccc1Cl
Reactant: COC(=O)C(C)(C)CO
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)NCc1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1 g, 7.31 mmol) and 2-chlorobenzylamine (1 mL, 8.75 mmol, 1.2 equiv.) in toluene (7 mL) was added trimethylaluminum (2 M in hexane, 5.4 mL, 10.8 mmol, 1.5 equiv.). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3. The resulting mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (1.5 g, 85%), which was used without further purification. LRMS (M+H+) m/z 242.1.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH3:22]
Reactant: CCCCCCCCCCCCN
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-dodecylamine (1.049 g, 5.59 mmol), triethylamine (0.86 ml, 6.15 mmol) and acetyl chloride (0.44 ml, 6.15 mmol) in dichloromethane (10 ml) was stirred at room temperature for 3h. The mixture was quenched with water and the organic phase was separated. Evaporation of the dried (magnesium sulfate) organic phase gave a solid, which was recrystallized from hexane to give the titled amide.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][C:28](O)([CH3:31])[CH2:29][OH:30]>>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH2:16][O:17][C:28]([CH3:31])([CH3:27])[CH2:29][OH:30])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CC(C)(O)CO
Product: CC(C)(CO)OCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F

Procedure:
Using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5, formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 as a starting material, and 2-methyl-propane-1,2-diol obtained in Step A instead of ethylene glycol used as a reagent in Step G of Example 1, synthesis similar to that in Step G of Example 1 was performed. The resultant cyclic acetal was subjected to reduction condition similar to that in Step H of Example 1 to give the title compound.
Reaction SMILES: [O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3][Cl:4].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CCOCC>O1CCOCC1>[ClH:4].[O:1]=[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:3][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cl
Product: O=C1CCc2cc(C(=O)CN3CCOCC3)ccc2N1
Reaction time: 12 h

Procedure:
5.0 Grams of 6-(1-oxo-2-chloroethyl)-3,4-dihydrocarbostyril and 6.0 g of morpholine were dispersed in 120 ml of dioxane and stirred at 60°-70° C. for 12 hours. The reaction mixture was concentrated under a reduced pressure. The residue thus obtained was stirred with ether and the insoluble matter was collected by filtration and washed with water. Then the insoluble matter was dissolved in 80 ml of methanol and 10 ml of concentrated hydrochloric acid by heating and the solution was concentrated under a reduced pressure to dryness. The residue thus obtained was recrystallized from methanol-ether twice and obtained 5.9 g of 6-(1-oxo-2-morpholinoethyl)-3,4-dihydrocarbostyril monohydrochloride in colorless powdery product.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.O>C(OCC)C>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2cc(C(=O)O)ccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1oc2cc(CO)ccc2c1C
Yield: 100 %

Procedure:
2,3-Dimethylbenzofuran-6-carboxylic acid (20.0 g, 0.105 mol) was added portionwise to a stirred suspension of lithium aluminium hydride (4.0 g., 0.105 mol) in anhydrous diethyl ether (800 cm3) and the mixture was heated under reflux for 4 hr. Ethanol and water were added and the mixture was filtered. The filtrate was dried (NaSO4), filtered and the solvent was removed to give 2,3-dimethyl-6-hydroxymethylbenzofuran (18.5 g, 0.105 mol, 99.9%), m.p. 78°-79° C. (ex aqueous ethanol).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(Cl)Cl>[Br:1][C:7]1[CH:6]=[C:5]([CH2:3][CH3:4])[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: CCc1ccc(O)cc1
Reactant: BrBr
Solvent: ClCCl
Product: CCc1ccc(O)c(Br)c1
Reaction time: 0.08 h
Yield: 9.5 %

Procedure:
Bromine (11.6 mL, 0.23 mol) was added slowly to a cooled 0° C. of 4-ethylphenol (2 g, 0.21 mol) dissolved in CH2Cl2 (125 mL). After the addition was complete the reaction mixture was stirred for 5 mins and then quenched with 1N NaOH. The reaction mixture was diluted with H2O and the layers separated. The organic layer was concentrated to an orange oil. Purification by flash column chromatography (0% to 5% EtOAc in hexanes) gave the title compound as a clear oil (4 g, 98%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 2.58 (q, J=7.5 Hz, 2 H), 5.36 (s, 1 H), 6.93 (d, J=8.3 Hz, 1 H), 7.03 (d, J=8.3 Hz, 1 H), 7.28 (s, 1 H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)[CH:2]=[CH2:3].[CH2:9]([NH2:12])[CH2:10][CH3:11]>C(O)C>[CH2:1]([O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:12][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: CCCN
Reactant: C=CCOCC1CO1
Solvent: CCO
Product: C=CCOCC(O)CNCCC

Procedure:
Allylglycidyl ether (94.7 g.) is added with stirring to a solution of n-propylamine (98 g., 137 ml.) in ethanol (200 ml.). The mixture is heated under reflux for 18 hours and the solvent and excess of n-propylamine are distilled off. The residual oil is distilled and the fraction b.p. 79°-85°C. at 1 m.m. is collected to give 1-allyloxy-3-n-propylamino-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](O)(=[O:16])C.C(O)(=O)C.IC1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]1([O:16][CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[CH:4]1
Reactant: COc1ccc(O)c2ccccc12
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Ic1ccccc1
Solvent: CO
Product: COC1(OC)C=CC(=O)c2ccccc21

Procedure:
For example, a solution of 4-methoxynaphthol (16 mmol) and iodobenzene diacetate (6.1 g, 19 mmol) in methanol (75 mL) is stirred at room temperature, under a nitrogen atmosphere for 1 hour. The resultant dark blue solution is poured into a saturated solution of NaHCO3 (75 mL), then evaporated to reduced volume. The blue oil is extracted with CH2Cl2 (3×75 mL) and the organic layer is washed with water (3×75 mL), brine (2×75 mL), and is dried over MgSO4, and filtered and evaporated to dryness (bath temp. <40° C.) to yield the product as a dark blue semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:19][CH:18]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:31])[NH:7][C:6]=2[CH:32]=1.O>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][N:26]5[CH2:27][CH2:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)[N:14]=[CH:15][C:10]=3[CH2:9][C:8](=[O:31])[NH:7][C:6]=2[CH:32]=1
Reactant: O=C1Cc2cnc(Nc3ccc(C#CCN4CCCC4)cc3)nc2-c2ccc(Cl)cc2N1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cnc(Nc3ccc(CCCN4CCCC4)cc3)nc2-c2ccc(Cl)cc2N1
Temperature: 22 °C
Reaction time: 12 h

Procedure:
To a solution of 9-chloro-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7H benzo[b]pyrimido[4,5-d]azepin-6-one (I-47) (0.082 g, 0.19 mmol) in EtOH (5 mL) was added Pd/C (10% wt, ˜50% H2O, 0.01 g) and the mixture was placed under H2 (1 atm) and stirred for 12 h at 22° C. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo to give crude product as a yellow oil. Purification by C-18 RP LC-MS chromatography afforded I-66 (0.046 g, 56%): HRMS Calcd. for C25H26ClN5O: 448.1904, Found 448.1907.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2coc3ccccc23)C1
Reactant: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(C2=CCN(CCc3coc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzofuran-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (342 mg, 1 mmol) (obtained from example 1, step 6) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 280 mg (78%); 357 (M+H); 1H NMR: δ□7.94 (d, 1H), 7.6 9 (d, 1H), 7.5–7.0 (m, 8H), 6.2 (bs, 1H), 3.8 (s, 3H), 3.49 (bs, 2H), 3.0 (m, 2H), 2.85 (m, 4H), 2.6 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].N1C=CC=CC=1.[Br:17][CH2:18][CH2:19][OH:20]>ClCCl>[Br:17][CH2:18][CH2:19][O:20][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCCBr
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCBr)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of 3-chlorobenzoyl chloride (2) (0.21 g, 2.8 mmol) and pyridine (0.46 mL, 5.7 mmol) in anhydrous dichloromethane (10 mL) at room temperature was (dropwise) added 2-bromoethanol (1) (0.23 mL, 3.1 mmol). The reaction mixture was stirred for 2 h at room temperature and quenched with 1N HCl. The organic phase was washed with saturated aqueous solution of NaHCO3, brine and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-bromoethyl 3-chlorobenzoate (3) as colorless oil (0.64 g). 1H NMR (CDCl3): δ 8.04 (t, J=1.8 Hz, 1H), 7.98-7.93 (m, 1H), 7.58-7.52 (m, 1H), 7.40 (t, J=8.4 Hz, 1H), 4.63 (t, J=6.0 Hz, 2H), 3.64 (t, J=6.0 Hz, 2H)