Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:3]1=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:34](=[O:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:3]1=[O:25])[CH3:24]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(NC(=O)Cc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-1-ethoxycarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C: m.p. 205°-207° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc4[nH]ncc34)ccn2c1=O
Yield: 87 %

Procedure:
Methyl 8-(1H-indazol-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A′ from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 1H-Indazole-4-boronic acid (67 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (110.5 mg, 79%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16]1([C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH2:24]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O1CCCC1>[C:16]1([C:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH2:24][S:1][C:2]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCC=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(F)(F)F)ccc1SCC=C(c1ccccc1)c1ccccc1
Yield: 85.2 %

Procedure:
A solution of 2.19 g (9.86 mmol) of methyl 2-mercapto-5-trifluoromethylbenzoate, 2.29 g (10.0 mmol) of 1,1-diphenyl-3-chloro-1-propene, and 1.67 g (11.0 mmol) of diazabicycloundecene (DBU) in 10 ml tetrahydrofuran was stirred for 60 minutes at room temperature. The solution was partitioned between ether and water and the ether layer was washed with water, dried over MgSO4 and evaporated. The residue was chromatographed (20% CH2Cl2 -hexane) on silica to afford 3.6 g (85%) of a clear oil. NMR (CDCl3, 90 MHz) 3.67 (d, 2H, J=8, CH2), 3.92 (s, 3H, --OCH3), 6.05 (t, 1H, J=8), 6.9-7.6 (m, 12H), 8.13 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1([CH3:37])[CH2:9][CH2:8][N:7]([C:10]2[C:19]([F:20])=[C:18]3[C:13]([C:14](=[O:29])[C:15]([C:24]([O:26]CC)=[O:25])=[CH:16][N:17]3[CH:21]3[CH2:23][CH2:22]3)=[C:12]([NH:30]C(OCC)=O)[C:11]=2[F:36])[CH2:6]1)(=O)C.[OH-].[Na+].[ClH:40]>C(O)C>[ClH:40].[NH2:30][C:12]1[C:11]([F:36])=[C:10]([N:7]2[CH2:8][CH2:9][C:5]([NH2:4])([CH3:37])[CH2:6]2)[C:19]([F:20])=[C:18]2[C:13]=1[C:14](=[O:29])[C:15]([C:24]([OH:26])=[O:25])=[CH:16][N:17]2[CH:21]1[CH2:23][CH2:22]1
Reactant: CCOC(=O)Nc1c(F)c(N2CCC(C)(NC(C)=O)C2)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(N)CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of ethyl 7-(3-acetylamino-3-methyl1-pyrroldinyl)-1-cyclopropyl-5-ethoxycarbonylamino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 20% aqueous sodium hydroxide, and ethanol was refluxed for 12 hours. The reaction mixture was treated with activated carbon and adjusted at pH 1-2 with 10% hydrochloric acid. After cooling, the resulting crystals were collected by filtration and recrystallized from water-ethanol to give 5-amino-7-(3-amino-3-methyl-1-pyrroldinyl)-1-cyclopropyl6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, m.p. 293°-297° C. (decomp.).
Reaction SMILES: C[O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Se](=O)=O.[O:15]1CCOC[CH2:16]1>O>[OH2:2].[CH3:16][O:15][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]([CH:3]=[O:2])=[O:5]
Reactant: COCC(=O)c1ccccc1
Reactant: C1COCCO1
Agent: O=[Se]=O
Solvent: O
Product: COc1ccccc1C(=O)C=O

Procedure:
A mixture of 4.5 g of 2-methoxyacetophenone, 4.33 g of selenium dioxide, 30 ml of dioxane and 3 ml of water is treated in the same manner as described in Example 5-(1). 5 g of 2-methoxyphenylglyoxal hydrate are thereby obtained as a crude oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:37])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([F:36])[CH:27]=2)=[CH:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:37])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[C:28]([F:36])[CH:27]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)c(F)c2)ccc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)c(F)c3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To 0.139 g (0.583 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.177 g (0.583 mmol) of 3-chloromethyl-6-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine (example 38C]), dissolved in 3 ml of abs. acetonitrile, was added 0.228 g of Cs2CO3 (0.700 mmol). The reaction mixture was stirred during 3 h at ambient temperature. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=88/12) yielded 0.219 g of pure title compound as white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)=[C:9]([C:19](O)=[O:20])[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1.C[CH2:29][N:30](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C1COCC1>CN(C=O)C.O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:22][C:8]=3[C:9]=2[C:19]([NH:30][CH3:29])=[O:20])=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(Cl)cc3)c(C(=O)O)c2cc1C1CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(Cl)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
To a solution of 5-cyclopropyl-2-(4-chlorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylic acid (5 g, 11.52 mmol) in dry DMF (30 mL) was added DIPEA (3.3 g, 25.34 mmol) and HATU (5.15 g, 13.5 mmol) at 20° C. After 15 minutes, 2M Methylamine in THF (23.04 mL, 46.08 mmol) was added dropwise and the mixture was stirred for another 2 hours before water (60 mL) was added. The mixture was extracted with EA (3×200 mL), washed with water (2×200 mL), dried and concentrated to afford 2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide as a brown solid (4.7 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (br. s., 1H) 8.45 (q, 1H) 7.90 (d, 2H) 7.53-7.64 (m, 3H) 7.16 (s, 1H) 3.06 (s, 3H) 2.83 (d, 3H) 2.21-2.37 (m, 1H) 0.94-1.05 (m, 2H) 0.64-0.73 (m, 2H). LCMS (m/z, ES+)=419 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=2)[C:7]([O:9][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[CH:20]=2)=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc(O)cc1C(=O)O
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)OCc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 5-hydroxy-2-methylbenzoic acid (1.0 g, 6.6 mmol) in DMF (50 ml) were added potassium carbonate (1.82 g, 13.14 mmol, 2.0 eq) and 3-chlorobenzyl bromide (1.72 g, 13.14 mmol, 2.0 eq). The mixture was stirred at 70° C. for 2 hours and then left stirring at room temperature overnight. The temperature was increased to 80° C. and heating continued for a further 6 hours. After cooling the mixture was diluted with ethyl acetate (200 ml) and washed with water (2×200 ml). Organic layer was separated, dried over MgSO4, filtered and evaporated to dryness to afford the title compound as a yellow oil, 2.67 g (contains 24% of monoalkylated phenol impurity). No further purification carried out. MS (ES−) m/z 399 [M−H]− (C22H1835Cl2O3). 1H-NMR (400 MHz, CDCl3) δ 2.52 (3H, s), 5.04 (2H, s), 5.29 (2H, s), 7.02 (1H, dd, J 8.4, J 2.8), 7.16 (1H, d, J 8.4), 7.29-7.34 (6H, m), 7.43 (2H, d, J 1.2), 7.54 (1H, d, J 2.8).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:41])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O>CCCCCC.C(OCC)(=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:21]([CH2:20][CH2:19][C:18]([OH:41])=[O:17])[CH:26]=1)(=[O:29])[CH3:28]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOS(C)(=O)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(C)=O)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 11 and starting with 0.2 g (1 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.39 g (1 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester (from example 32), 5-acetyl-2-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid was obtained in 64.3% overall yield, as a colorless solid, mp 115°-118° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[C:13]([O:20][CH3:21])[CH:12]=2)=[C:5](Cl)[N:4]=1>[Hg](Cl)Cl.[Zn].C(O)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:12]=[C:13]([O:20][CH3:21])[C:14]([NH2:19])=[C:15]([O:17][CH3:18])[CH:16]=2)=[CH:5][N:4]=1
Reactant: COc1cc(Cc2c(N)nc(N)nc2Cl)cc(OC)c1N
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Reaction time: 8 h

Procedure:
A solution of 0.1 g. of mercury (II) chloride in 2 ml. of water and 1.5 g. of zinc powder was added to a solution of 1.5 g. of 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-6-chloropyrimidine in 15.5 ml. of glacial acetic acid and the mixture was boiled under reflux with stirring overnight. Then, the mixture was filtered while hot and the zinc powder washed with 5 ml. of acetic acid. The combined filtrates were added dropwise with stirring at a temperature below 20° C. to 40 ml. of concentrated ammonia. Then, the mixture was stirred at 20° C. for an additional hour and the solid material was removed by filtration under vacuum, washed with water, dried, recrystallized from methanol and there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine having a melting point of 214° C.
Reaction SMILES: [NH:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=2)=[CH:7][CH:6]=1)C(C)=O.[ClH:22]>>[ClH:22].[ClH:22].[NH2:1][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(Cc2ccc(NC(C)=O)cc2)cn1
Agent: Cl
Product: Nc1ccc(Cc2ccc(C(=O)O)nc2)cc1

Procedure:
0.8 Gram of methyl 5-(4-acetaminobenzyl)picolinate and 20 ml. of concentrated hydrochloric acid were heated under reflux for 3 hours. Then, concentrated hydrochloric acid was distilled out under reduced pressure. Ethyl alcohol was added thereto and thus resulting crystals were collected by filtration and dried at room temperature under reduced pressure to obtain 0.7 g of 5-(4-aminobenzyl)picolinic acid dihydrochloride as colorless crystals of a decomposition point of 217°-223° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][C:14](=[O:17])[CH2:15][CH3:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1cc(C(CC(=O)CC)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reaction time: 5 h

Procedure:
A mixture of N-{2-[1-(3ethoxy-4-methoxyphenyl)-3-hydroxypentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.35 g, 3.06 mmol), pyridinium chlorochromate (1.32 g, 6.12 mmol) and celite (0.6 g) in methylene chloride (35 mL) was stirred for 5 hours. The mixture was filtered through celite and the filtrate was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. Solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give N-{2-[1-3-ethoxy-4-methoxyphenyl)-3-oxopentyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.08 g, 81%) as a white solid: mp 137-139° C.; 1H NMR (CDCl3) δ 9.53 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.07-7.04 (m, 2H), 6.83 (d, J=8.8 Hz, 1H), 5.76-5.70 (dd, J=5.2, 10.1 Hz, 1H), 4.12 (q, J=6.9 Hz, 2H), 4.02-3.90 (dd, J=10.1, 17.9 Hz, 1H), 3.83 (s, 3H), 3.26-3.17 (dd, J=5.2, 17.9 Hz, 1H), 2.49 (q, J=7.3 Hz, 2H), 2.26 (s, 3H), 1.46 (t, J=6.9 Hz, 3H), 1.02 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3) δ 208.03, 170.02, 169.15, 167.86, 149.12, 148.33, 137.34, 135.76, 131.39, 131.22, 124.64, 120.00, 117.87, 115.29, 112.50, 111.27, 64.38, 55.89, 49.94, 43.51, 36.10, 24.92, 14.71, 7.52; Anal. Calcd. for C24H26N2O6: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.74; H, 6.34; N, 6.38.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][NH:36][CH3:37]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:36]([CH3:37])[CH3:35])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CNC
Solvent: CCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN(C)C)c(OC)cc23)c2c1OCO2
Yield: 77 %

Procedure:
N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and dimethylamine (5 ml of a 33% solution in ethanol) were stirred and heated under reflux at 90° for 30 min. before evaporating the solution. A further 5 ml of dimethylamine solution were added to the residue and the solution heated for a further 90 min. then evaporated. Again a further 5 ml of dimethylamine solution were added to the residue and the solution heated for 1 hr. before quenching in water and extracting with dichloromethane. The extract was washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. It was then purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (156 mg, 77%) as a pale orange solid; NMR Spectrum:(DMSOd6) 1.95 (quintet, 2H), 2.17 (s, 6H), 2.38 (t, 2H), 2.71 (t, 2H), 3.30 (s, 3H), 3.52 (t, 2H), 3.92 (s, 3H), 4.17 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.81 (s, 1H), 8.31 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 513/515.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:29])=[O:5])[CH3:2].C(N(CC)CC)C.[C:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)(=[O:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:37]([N:40]1[CH2:45][CH2:44][CH:43]([N:20]2[CH2:21][C:16]3[C:15]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])=[N:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:8]([F:29])[CH:9]=4)=[N:18][C:17]=3[CH2:19]2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1F
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCN(C(C)=O)CC2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
To (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (intermediate 18) (100 mg, 0.23 mmol) and triethylamine (64 μL, 0.46 mmol) in dry THF (3 ml) was added 1-acetylpiperidin-4-one (56 μL, 0.46 mmol) and stirred at room temperature for 30 min. To this sodium triacetoxyborohydride (97 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. The solvent was then removed in vacuo. Crude reaction mixture then was partitioned between ethyl acetate and water. The organic layer was recovered, dried with sodium sulphate and solvent removed in vacuo. Residue was then purified by prep HPLC (low pH) to afford a white solid (6.7 mg, 0.013 mmol, 6%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[C:16]=1[F:22])(C)(C)C>C(Cl)Cl>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([NH2:14])[CH:20]=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
TFA (5 mL) was added to a solution of (2-chloro-3-fluoropyridin-4-yl)carbamic acid tert-butyl ester (1.9 g, 7.7 mmol) in DCM (10 mL). The solution was stirred at ambient temperature for 5 hours and concentrated under reduced pressure. The resultant residue was dissolved in DCM and purified by column chromatography on a NH2 cartridge (0-10% MeOH in DCM) to afford the title compound as a beige solid (0.96 g, 94% yield). 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J=5.4 Hz, 1H), 6.60 (t, J=5.8 Hz, 1H), 4.38 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CO[CH:11]=[C:12]1[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]1=[O:21]>C(O)(C)C>[Cl:8][C:3]1[C:2]([NH:1][CH:11]=[C:12]2[C:13](=[O:21])[O:14][C:15]([CH3:19])([CH3:20])[O:16][C:17]2=[O:18])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: Nc1cccnc1Cl
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(=CNc2cccnc2Cl)C(=O)O1
Yield: 89.9 %

Procedure:
A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH2:3]1.I[CH2:15][CH:16]([CH3:18])[CH3:17]>>[O:13]=[C:4]1[N:5]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:2](=[O:1])[CH2:3]1
Reactant: O=C1CC(=O)Nc2ccccc2N1
Reactant: CC(C)CI
Product: CC(C)CN1C(=O)CC(=O)N(CC(C)C)c2ccccc21

Procedure:
2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A and 1-iodo-2-methylpropane (Aldrich). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to 1:1), then recrystalization from EtOAc/hexanes.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: NCCc1ccccc1
Solvent: CO
Product: COC(=O)CCNCCc1ccccc1
Reaction time: 4 h
Yield: 76.2 %

Procedure:
Phenethylamine (121 g) is dissolved in methanol (500 ml) and thereto is added dropwise methyl acrylate (86 g) at room temperature. The mixture is stirred for 4 hours and then distilled to remove the solvent to give N-phenethyl-β-alanine methyl ester (157.8 g, 76%), b.p. 124°-127° C. (1.2 mmHg).