Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.Cl.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1.CCN(CC)CC.Cl>CN(C=O)C.O>[OH:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[CH2:18][CH2:19]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(trifluoromethoxy)phenyl isocyanate (2 g, 9.8 mmol) in DMF (100 mL) were added trans-4-aminocyclohexanol hydrochloride (1.6 g, 10.8 mmol) and Et3N (1.5 mL, 10.8 mmol) at 0° C. The reaction mixture was warmed up to room temperature and stirred overnight. After adding aq 1N HCl (20 mL) and water (100 mL), the resulting white precipitates were collected by suction filtration. The collected solid was thoroughly washed with water. Recrystallization from acetone at −78° C. afforded 2.4 g (70%) of the title compound as a white solid. mp 224.1-225.3° C. 1H NMR (300 MHz, DMSO-d6; δ 8.50 (s, 1H), 7.45 (d, J=9 Hz, 2H), 7.21 (d, J=9 Hz, 2H), 6.06 (d, J=8 Hz, 1H), 4.55 (d, J=4 Hz, 1H), 3.44-3.33 (m, 2H), 1.91-1.68 (m, 4H), 1.31-1.07 (m, 4H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Oc5ccc(Cl)cc5)c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-chlorophenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-chlorophenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([CH2:10][N:11]=[N+:12]=[N-:13])=[C:8]([CH3:14])[N:7]=[CH:6]1)([OH:3])=O.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([NH:19][C:1]([CH2:4][N:5]1[C:9]([CH2:10][N:11]=[N+:12]=[N-:13])=[C:8]([CH3:14])[N:7]=[CH:6]1)=[O:3])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ncn(CC(=O)O)c1CN=[N+]=[N-]
Reactant: CC(C)(C)N
Product: Cc1ncn(CC(=O)NC(C)(C)C)c1CN=[N+]=[N-]

Procedure:
The title compound was prepared from 1-carboxymethyl-4-methyl-5-azidomethylimidazole and tert-butylamine using the procedure described in EXAMPLE I, Step A. 1H NMR (CDCl3) d 1.32 (s, 9 H), 2.29 (s, 3 H), 4.31 (s, 2 H), 4.48 (s, 2 H), 5.25 (br s, 1 H), 7.47 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:35]=2)=[O:33])[CH:27]=[CH:28][C:29]=1[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:23][C:24]2[CH:25]=[C:26]([NH:31][C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[CH:35]=3)=[O:33])[CH:27]=[CH:28][C:29]=2[CH3:30])=[O:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)C1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)C2)c1

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 26, 3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzoic acid was reacted with N-(3-amino4-methylphenyl)-2-morpholinopyridine4-carboxamide to give N-{3-[3-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzamido]-4-methylphenyl}-2-morpholinopyridine-4-carboxamide; NMR Spectrum: (DMSOd6) 1.42 (s, 9H), 2.15 (s, 2H), 2.22 (s, 3H), 3.44 (m, 3H), 3.55 (t, 4H), 3.6 (m, 1H), 3.77 (t, 4H), 5.18 (m, 1H), 7.13 (d, 1H), 7.21 (m, 1H), 7.37 (m, 2H), 7.5 (t, 1H), 7.56 (s, 1H), 7.61 (d, 2H), 7.81 (d, 1H), 8.3 (d, 1H), 9.9 (s, 1H), 10.31 (s, 1H); Mass Spectrum: M+H+ 602.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:10]1[NH:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:8].C(O)(=O)C.O.[OH-].[NH4+]>[Pd].C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[NH:11][C:12](=[O:21])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[CH3:8]
Reactant: COc1ccc(C(=O)NC2C=CC=CC2=C(C)c2ccccn2)cc1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccccc2C(C)c2ccccn2)cc1

Procedure:
2'-[1-(2-Pyridyl)-ethylidene]-p-anisanilide (6.0 g., 0.018 mole) is reduced in a Parr apparatus in 100 ml. of acetic acid employing 1.0 g. of 10% palladium on carbon catalyst. The catalyst is collected, the filtrate concentrated under reduced pressure and the residue thus obtained distributed between water and ethyl acetate. This mixture is made basic with concentrated ammonium hydroxide and the ethyl acetate extract separated, dried, and concentrated to provide 2'-1-(2-pyridyl)ethyl-p-anisanilide, m.p. 125°-126° C. (corr.), from aqueous ethanol.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:36])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=2[CH3:35])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pd]>[NH2:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]2[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:21]2=[O:36])=[C:27]([CH3:35])[CH:28]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
555 mg (1.11 mmol) of the compound from Example 7A are dissolved in 15 ml of THF, 150 mg of palladium on carbon are added and the mixture is hydrogenated in a hydrogen atmosphere at atmospheric pressure until the theoretical amount of hydrogen has been taken up. The catalyst is filtered off, which gives, after concentration under reduced pressure, 520 mg (99% of theory) of the title compound.
Reaction SMILES: N[C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1.C=O.[C:19](#N)C.[C:22]([BH3-])#[N:23].[Na+]>C(O)(=O)C>[CH3:19][N:23]([CH3:22])[C:2]1[CH:16]=[CH:15][C:5]2[CH:6]=[CH:7][N:8]3[CH:14]=[CH:13][CH:12]=[C:9]3[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1ccc2ccn3cccc3c(=O)c2c1
Reactant: [BH3-]C#N
Reactant: CC#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1ccc2ccn3cccc3c(=O)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of 9-amino-11H-pyrrolo[2,1-b][3]benzazepin-11-one (2.1 g., 10 mmoles) and 4 ml. (50 mmole) of 37% aqueous formaldehyde in 15 ml. of acetonitrile is added 1 g. (16 mmoles) of sodium cyano borohydride. A vigorous and exothermic reaction takes place and a dark residue separates. The mixture is stirred for 15 mins. and then glacial acetic acid is added dropwise until the solution tests neutral on wet pH paper. Stirring is maintained for an additional 2 hrs. The volatiles are removed under vacuum, and the residue is dissolved in chloroform. The solution is washed with base and with water, dried over sodium sulfate, and concentrated to leave a residue that is purified by chromatography on silica gel. Elution with chloroform yields 9-dimethylamino-11H-pyrrolo[2,1-b][3]benzazepin-11-one as a dark brown oil.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:53][C:54]1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[O:56][C:55]=1[C:63](O)=[O:64]>CN(C=O)C.O>[CH3:53][C:54]1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[O:56][C:55]=1[C:63]([N:16]1[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]2/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/2)[CH2:14][CH2:15]1)=[O:64]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2oc3ccccc3c2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (500 mg) in DMF (10 mL) were added N-ethyl-N-(1-methylethyl)propan-2-amine (1.40 mL), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (708 mg), and 3-methylbenzofuran-2-carboxylic acid (335 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (625 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][NH:29][CH2:26][CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 92.3 %

Procedure:
0.94 g (2.5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one was stirred at room temperature overnight with 1 g (17 mmol) of propylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there was obtained 0.92 g (92%) of (S)-8-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 237°-239°, which was converted into the hydrochloride.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:25]3[CH2:26][CH:27]=[C:28]([C:31]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[CH2:29][CH2:30]3)[O:18][C:17]=2[CH:19]=1
Reactant: COc1ccc2c(c1)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2

Procedure:
[(2R)-7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (1.5 g, 4.3 mmole) was dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 30 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 4.0 mmole) added, followed by sodium bicarbonate (1.0 g), and the mixture was refluxed under nitrogen for 18 hours. The solvent was removed under vacuum and the residue partitioned between 400 mL each of methylene chloride and water. The layers were separated and the organic phase was washed with water and saturated sodium chloride solution, dried over potassium carbonate and filtered. The filtrate was evaporated to a foam (1.6 g). Chromatography on silica gel using 4% methanol in chloroform as eluant gave 0.20 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 166–168° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl.[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1.O>CN(C)C=O>[NH2:22][C:23]1[C:38]([Cl:39])=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:32][CH2:33][N:34]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:35][CH2:36]2)=[O:28])=[C:25]([O:40][CH3:41])[CH:24]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccccc2)CC1
Reaction time: 7.5 h
Yield: 44.1 %

Procedure:
Potassium carbonate (2.2 g) and 5-phenoxypentyl chloride (1.2 g) were added to a solution of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) in dimethylformamide (40 ml), an the mixture was stirred at 70°-80° C. for 7.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=5:1) to give crystals. The obtained crystals were recrystallized from ethyl acetate to give 0.82 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenoxypentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:36]([O-])=O)=[C:4]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1>[Pd]>[NH2:36][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3cccc(F)c3[N+](=O)[O-])nc21
Agent: [Pd]
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3cccc(F)c3N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a mixture of 2-{1-[2-(3-fluoro-2-nitrophenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (95 mg, 0.18 mmol) in IMS (5 mL) was added 10% Pd on charcoal (20 mg) under an argon atmosphere. The vessel was evacuated and backfilled with hydrogen (the process was repeated three times). The reaction mixture was stirred at room temperature for 18 hours then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was subjected to flash chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give 2-{1-[2-(2-Amino-3-fluoro-phenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol as a red oil (65 mg, 72%). LCMS (Method H): RT=0.28 min and 2.82 min, [M+H]+ 499
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:46]=[CH:47][C:48]=1[O:49][CH3:50])[CH2:28][O:29][C:30]([NH:32][C:33]1[N:41]=[CH:40][N:39]=[C:38]2[C:34]=1[N:35]=[CH:36][N:37]2[CH2:42][C:43](O)=[O:44])=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:43](=[O:44])[CH2:42][N:37]1[CH:36]=[N:35][C:34]2[C:38]1=[N:39][CH:40]=[N:41][C:33]=2[NH:32][C:30]([O:29][CH2:28][C:27]1[CH:46]=[CH:47][C:48]([O:49][CH3:50])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:31])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ncnc3c2ncn3CC(=O)O)cc1OC
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc(OC)c(OC)c3)ncnc21
Yield: 97.6 %

Procedure:
The title compound (6.28 g, 96%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (3.26 g, 9.5 mmol) and [6-N-(3,4-dimethoxybenzyloxycarbonyl)-adenin-9-yl]-acetic acid (3.50 g, 9.03 mmol) as per the procedure of Example 27. 1H NMR (500 MHz; DMSO-d6) 10.58 (s, 1H), 8.98 (brs, 0.6H), 8.77 (brs, 0.4H), 8.57 (s, 0.4H), 8.53 (s, 0.6H), 8.29 (d, 1H), 8.27 (m, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 7.08 (s, 1H), 6.98 (d, 1H), 6.94 (d, 1H), 5.35 (s, 1.2H), 5.15 (s, 0.8H), 5.12 (s, 2H), 4.45 (s, 0.8H), 4.18 (q, 0.8H), 4.07 (s, 1.2H), 4.01 (q, 1.2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.70 (t, 1.2H), 3.48 (t, 1.2H), 3.42 (t, 0.8H), 3.22 (t, 0.8H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: C([O:3][CH2:4]CN1C2C=NC=CC=2N=C1CN1CCNCC1)C.Br[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[N:28](CC)[N:27]=[N:26]1.[C:33](=[O:36])([O-:35])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[C:4]([OH:3])(=[O:30])[C:33]([OH:35])=[O:36].[CH2:24]([N:25]1[C:29](=[O:30])[NH:28][N:27]=[N:26]1)[CH3:23]
Reactant: CCn1nnn(CCBr)c1=O
Reactant: O=C([O-])[O-]
Reactant: CCOCCn1c(CN2CCNCC2)nc2ccncc21
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1nn[nH]c1=O
Product: O=C(O)C(=O)O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2.7 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-3H-imidazo [4,5-c]pyridine, 2.7 parts of 1-(2-bromoethyl)-4-ethyl-1,4-dihydro -5H-tetrazol-5-one, 1.3 parts of sodium carbonate and 72 parts of N,N-dimethylacetamide was stirred overnight at 70° C. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted into the ethanedioate salt in 2-propanol. The salt was filtered off and dried, yielding 3.9 parts (64.0%) of 1-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl ]methyl]-1-piperazinyl]ethyl)]-4-ethyl-1,4-dihydro-5H-tetrazol-5-one ethanedioate(1:2); mp. 170.9° C. (compound 38).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:18](O)(=[O:20])[CH3:19].C(OC(=O)C)(=O)C>CCOCC>[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
A mixture of 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 200 ml of acetic acid, and 10.5 ml (110 mmol) of acetic anhydride is heated at reflux for 4.5 hrs. The mixture is cooled and diluted with 150 ml of ether. The solid is filtered, washed with ether, and dried at 60° to give 13.6 g of 6-[4-(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>260°.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:10])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[NH2:10][C:3]1[C:2](/[CH:13]=[CH:12]/[C:11]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[N:4]=1
Reactant: COc1ncc(Cl)c(N)n1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(OC)nc1N
Temperature: 122.5 °C
Reaction time: 5 h

Procedure:
To 2.9 g of 5-chloro-2-methoxypyrimidin-4-amine, 2.35 mL of ethyl acrylate, 18 mL of triethylamine, and 0.46 g of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at an external temperature of 115 to 130° C. for 5 hours in a sealed tube. Thereto were further added 5 mL of triethylamine, 0.30 g of bis(tri-tert-butylphosphine)palladium(0) and 0.5 mL of ethyl acrylate, and the mixture was stirred at an external temperature of 120 to 130° C. for 6 hours 30 minutes in a sealed tube. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, and the aqueous layer was extracted with chloroform and ethyl acetate. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.89 g of ethyl (2E)-3-(4-amino-2-methoxypyrimidin-5-yl)acrylate as a yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][N:18]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:28]=3[CH3:29])[C:19]2=[O:22])=[CH:14][C:13]=1[OH:30].C1(N[S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])C=CC=CC=1.CO>C1COCC1.C(Cl)(Cl)Cl>[F:42][C:41]([F:44])([F:43])[S:38]([O:30][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[Cl:11])[C:19](=[O:22])[N:18]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:17][CH2:16]2)(=[O:40])=[O:39]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: Cc1ccncc1N1CCc2cc(O)c(Cl)cc2C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)cc2C1=O
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
KHMDS (0.23 mL (0.91M), 0.21 mmol) was added to a solution of 7-chloro-6-hydroxy-2-(4-methylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (87A: 50 mg, 0.1736 mmol) in THF (5 mL) at −78° C. and stirred at −10° C. for 20 minutes, then cooled to −78° C., followed by the addition of N-phenyl trifluoromethanesulfonamide (68.2 mg, 0.190 mmol). The resulting mixture was stirred at room temperature for 60 minutes. The reaction was monitored by TLC (5% methanol in CHCl3). The reaction mixture was quenched with saturated NH4Cl solution and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 50 mg of the product (70% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([Cl:11])(Cl)=[O:9].[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CC1CCCCC1.C1(C)C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([Cl:11])=[O:9]
Reactant: O=C(Cl)Cl
Reactant: CCCCCNC
Solvent: CCN(CC)CC
Solvent: CC1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCN(C)C(=O)Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Triethylamine (14 cc.) is added over the course of 8 minutes to a 2.5N solution (42 cc.) of phosgene in methylcyclohexane, cooled to -10° C., and a solution of N-methylpentylamine (13.7 cc.) in toluene (50 cc.) is then added whilst maintaining the temperature at -10° C. The mixture is stirred for 1 hour at +5° C. The insoluble material is then filtered off and washed with toluene (80 cc.). The organic solutions are dried over calcium chloride (10 g.). After filtration, the solvents are evaporated under reduced pressure (40 mm.Hg). The residue is distilled under reduced pressure to give N-methyl-N-pentylcarbamoyl chloride (5.6 g.), b.p. 120°-125° C./40 mm.Hg.