Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1>[Pd].CO>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]2[CH3:1]
Reactant: Cc1cc2c([N+](=O)[O-])cccc2c(C)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(N)cccc2c(C)n1

Procedure:
A solution of D3 (2.01 g, 9.94 mM) and 10% palladium on charcoal (1 g) in methanol was hydrogenated at atmospheric pressure for 1 h. The catalyst was filtered off and the filtrate concentrated under reduced pressure to afford the title compound as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[N:21]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)C.C1C=CC=CC=1>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=3)[C:25]([C:22]3[CH:23]=[CH:24][NH:20][N:21]=3)=[N:1][C:2]=2[CH:17]=1
Reactant: COc1ccc(Nc2ccc(CCO)cc2)c(N)c1
Reactant: O=Cc1cc[nH]n1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc2c(c1)nc(-c1cc[nH]n1)n2-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A mixture of 2-(4-{[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. After cooling, the mixture was concentrated. A mixture of the residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at room temperature for 16 h. The mixture was quenched with saturated NaHCO3 aqueous solution (150 ml). The whole was extracted with ethyl acetate (150 ml×4). The organic layer was washed with water (100 ml×5), brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 408 mg (16%) of the title compound as an amber solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+].[N:46]1([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[N:46]1([CH:52]2[CH2:57][CH2:56][N:55]([CH2:27][CH2:28][S:29]([N:23]3[CH2:24][CH2:25][CH:20]([C:11]4[C:10]5[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:4]6[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=6)[CH:9]=5)[NH:13][N:12]=4)[CH2:21][CH2:22]3)(=[O:31])=[O:30])[CH2:54][CH2:53]2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCN4CCC(N5CCCCC5)CC4)CC3)n[nH]c12
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 33. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (75 mg, 0.167 mmol) was reacted with 2-chloro-1-ethanesulfonyl chloride (17 uL, 0.167 mmol) in the presence of triethyl amine (93 uL, 0.665 mmol) in DMF (2 mL) at 0° C. After 10 mins., K2CO3 (46 mg, 0.334 mmol) and 4-piperidino-piperidine (84 mg, 0.501 mmol) were added to afford the title compound (22.6 mg, 23% for 2 steps).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[N:4]=[C:3]1[NH:14]N>NCCCCO>[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[N:4]=[C:3]1[NH:14][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: Cc1ccc2nc(NN)n(N)c(=O)c2c1
Agent: NCCCCO
Product: Cc1ccc2nc(NCCCCO)n(N)c(=O)c2c1
Yield: 126.7 %

Procedure:
20 g of 3-amino-2-hydrazino-6-methylquinazolin-4(3H)-one were stirred in 100 ml of 4-aminobutanol at 175° C. for 24 hours and the majority of the 4-aminobutanol was then distilled off under vacuum. The residue was diluted with water to crystallize out the product and the mixture was filtered. The product was washed and dried to obtain 16.2 g of 3-amino-2-(4-hydroxybutylamino)-6-methylquinazolin-4(3H)-one.
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:5].[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])#[N:22].Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>O1CCCC1>[C:21]([C:23]1[CH:24]=[C:25]([NH:26][C:31](=[O:33])[NH:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[O:5])[CH:27]=[CH:28][CH:29]=1)#[N:22]
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1cccc(N)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)c1
Yield: 204.3 %

Procedure:
A solution of the compound 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (10 ml) is added under ice cooling to a solution of m-bromoisocyanate which is prepared according to the method described in EP-508796-A1 from a solution of m-cyanoaniline (581 mg, 4.92 mmol), triphosgene (551 mg, 1.72 mmol) and triethylamine (960 μl, 6.9 mmol) in tetrahydrofuran (50 ml). In addition, triethylamine (558 μl, 4 mmol) is added and treated as in a manner similar to that described in Preparation 5 to prepare the compound 6w (1.4 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH2:7][N:8]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:34]([N:36]=[C:37]([N:39]1CCNCC1)[S-])#[N:35].O.[NH2:46]N>>[NH2:46][C:37]1[N:36]=[C:34]([N:23]2[CH2:22][CH2:21][CH:20]([N:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=3)[CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:25][CH2:24]2)[NH:35][N:39]=1
Reactant: O=C(NCCN(CCc1ccc(Cl)cc1)C1CCNCC1)c1ccccc1
Reactant: NN
Reactant: N#CN=C([S-])N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1n[nH]c(N2CCC(N(CCNC(=O)c3ccccc3)CCc3ccc(Cl)cc3)CC2)n1

Procedure:
N-(2-((4-Chlorophenethyl)(piperidin-4-yl)amino)ethyl)benzamide obtained in Step 4 was reacted with K2CO3 and S,S′-dimethyl-N-cyano-dithioiminocarbonate, followed by the cyclization of the intermediate (N-cyanopiperazine-1-carbimidothioate) with hydrazine monohydrate in a manner described in Procedure 3. Purification over silica gel provided pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([F:15])[CH:3]=1.[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][CH:26]2[CH2:28][O:27]2)=[O:23])=[CH:19][CH:18]=1.O>C(O)C>[Cl:16][C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][CH:26]([OH:27])[CH2:28][NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])=[C:4]([F:15])[CH:3]=2)=[O:23])=[CH:19][CH:18]=1
Reactant: O=C(NCC1CO1)c1ccc(Cl)s1
Reactant: Nc1ccc(N2CCOCC2=O)c(F)c1
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)CNc1ccc(N2CCOCC2=O)c(F)c1)c1ccc(Cl)s1

Procedure:
800 mg (3.8 mmol) of 4-(4-amino-2-fluorophenyl)-3-morpholinone and 700 mg (3.22 mmol) of 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide are heated in 15 ml of ethanol and 1 ml of water under reflux for 6 hours. The mixture is evaporated in vacuo, the crystals which have separated out after treatment with ethyl acetate are filtered off with suction, and chromatography of the mother liquor results in 276 mg (17% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].IC.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH3:14])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccccc1C=O

Procedure:
4.5 g (30 mmol) of 2-carboxybenzaldehyde, 17.1 (120 mmol) of iodomethane and 12.4 g (90 mmol) of potassium carbonate were stirred in 85 ml of acetone for 24 hours. The solvent was removed by evaporation and the residue was partioned between 50 ml of water and 50 ml of ether. The aqueous layer was washed with 3×50 ml portions of ether. The combined organic extracts were washed with 30 ml each of 1M sodium thiosufate and saturated sodium cloride solutions and dried over MgSO4. The solvent was removed by evaporation. The residue was subjected to flash chromatography (silica gel, 10% ethyl acetate/hexanes) to give the title compound as a clear colorles oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]=[C:5]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:6]=1.[N:18]([O-])=O.[Na+].[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([OH:32])=[O:31].[OH-].[Na+]>O.Cl>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([N:18]=[N:17][C:14]2[CH:13]=[CH:12][C:11]([S:8]([NH:7][C:5]3[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=3)(=[O:10])=[O:9])=[CH:16][CH:15]=2)=[CH:25][C:24]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: O=C(O)Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1cc(N=Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O

Procedure:
12 g sulfapyridine was dissolved with cooling to 0° C. in 40 ml water and 12 ml conc. hydrochloric acid. 3.5 g sodium nitrite in 20 ml water was added to the sulfapyridine solution during about 15 minutes with stirring and cooling. The diazonium salt solution was added to 7.6 g 2-hydroxy-benzeneacetic acid and 7 g sodium hydroxide in 50 ml water at 0°-10° C. After stirring for 1.5 h the solution was acidified by hydrochloric acid. The precipitating product was filtered off and washed with water. Yield 18.1 g. The product was dissolved in acetic acid and treated with 5 g decolourizing coal. The solution was filtered and evaporated in vacuum. This was repeated once, a pure product being obtained, which during partial melting at about 135° C. was converted into another crystal modification of melting point 185°-187° C. with decomposition.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[S:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:53]CCl>CO.C(Cl)(Cl)Cl>[ClH:53].[O:23]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[S:25][CH2:24]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)SCO2
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)SCO3)CC1

Procedure:
(2R)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (50 mg, 0.166 mmol) (for a preparation see Example 16(j)) and [1,3]oxathiolo[4,5-c]pyridine-6-carbaldehyde (25 mg, 0.901 eq.) were stirred in 9:1 v:v chloroform:methanol (1 ml) for 2.5 hours. Sodium triacetoxyborohydride (105 mg, 3.000 eq.) was then added in one portion and the mixture was stirred vigorously at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate (0.5 ML) was then added, followed by dichloromethane (10 ml) and the mixture was stirred vigorously at room temperature for 10 min and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (eluted with 0-12% (2M NH3 in MeOH) in DCM). Appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a pale yellow amorphous solid (48 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1[C:22]2[CH2:23][CH2:24][O:25][CH2:26][C:21]=2[CH:20]=[N:19][C:18]=1[N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.[CH:45]1[CH:46]=[CH:47][C:48]2[N:53](O)N=N[C:49]=2[CH:50]=1.CN1CCOCC1>O.CC(N(C)C)=O>[N:17]1[C:22]2[CH2:23][CH2:24][O:25][CH2:26][C:21]=2[CH:20]=[N:19][C:18]=1[N:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)[CH2:29][CH2:28]1.[CH3:47][CH:48]1[CH:49]=[CH:50][CH:45]([CH3:46])[N:53]1[C:26]([C:21]1[CH:22]=[CH:23][C:18]([N:27]2[CH2:28][CH2:29][CH:30]([NH:33][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][CH:10]=3)[CH2:31][CH2:32]2)=[N:19][CH:20]=1)=[O:25]
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)nc1
Reactant: On1nnc2ccccc21
Reactant: NC1CCN(c2ncc3c(n2)CCOC3)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: CC1C=CC(C)N1C(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Product: O=C(NC1CCN(c2ncc3c(n2)CCOC3)CC1)c1ccc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.4 %

Procedure:
To a vial was added, 6-(3-fluorophenyl)nicotinic acid (46.4 mg, 0.213 mmol), 1-(7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)piperidin-4-amine (50 mg, 0.21 mmol), EDAC (45.0 mg, 0.235 mmol), HOBT (28.8 mg, 0.213 mmol), and DMA (1 mL) followed by NMM (0.058 mL, 0.534 mmol). The reaction was stirred overnight at room temperature and then diluted with H2O and the resulting solid filtered and collected to give the desired product, N-(1-{5-[(2,5-dimethyl-2,5-dihydro-1H-pyrrol-1-yl)carbonyl]pyridin-2-yl}piperidin-4-yl)-6-(3-fluorophenyl)nicotinamide (81 mg, 88%). 1H NMR (400 MHz, DMSO-d6) □ ppm 9.06 (1H, s), 8.45 (1H, d, J=7.5 Hz), 8.21-8.30 (1H, m), 8.04-8.14 (2H, m), 7.89-8.02 (2H, m) 7.49-7.59 (1H, m), 7.29 (1H, t), 4.49-4.64 (5H, m), 4.11 (1H, br. s.), 3.89 (2H, t, J=5.9 Hz), 2.94-3.07 (2 H, m), 1.88 (2H, d, J=10.1 Hz), 1.42-1.56 (3H, m). HRMS (TOF, ES+) calculated for M+H: 434.1992; observed 434.2165.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[BrH:1].[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:5]=1
Reactant: Nc1ncc(Br)cc1Br
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: Br
Product: CCOC(=O)c1cn2cc(Br)cc(Br)c2n1
Yield: 139.9 %

Procedure:
A mixture of 3,5-dibromopyridin-2-amine (2.51 g, 10 mmol) and ethyl 3-bromo-2-oxopropanoate (2.5 g, 13 mmol) in THF (50 mL) was heated at reflux 48 hrs. The solution was evaporated and the residue triturated with ether and the resulting solid was filtered and dried to give ethyl 6,8-dibromoimidazo[1,2-a]pyridine-2-carboxylate hydrobromide (3.0 g, 69% yield). LCMS (Conditions C): 2.70 min (RT); (M+H)+=347.09 (60%), 349.09 (100%), 351. 08 (60%). 1H NMR, 400 MHz, CDCl3: δ 8.39 (d, 1.5 Hz, 1 H), 8.28 (s, 1 H), 7.67 (d, 1.5 Hz, 1 H), 4.46 (q, J=7.0 Hz, 2 H), 1.43 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.O>[NH:20]([C:21]([NH:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC1(CC(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1(NC(=O)Nc2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 55.7 %

Procedure:
To a solution of (1-aminocyclohexyl)acetic acid (0.232 mg, 1.48 mmol) in a mixture of 1,4-dioxane (9 ml) and water (3 ml) was added 30% aqueous sodium hydroxide solution to pH 9. Phenylisocyanate (0.24 ml, 2.22 mmol) was added dropwise at 35° C. and 30% aqueous sodium hydroxide solution was added to adjust the solution to pH9. The reaction mixture was stirred at 40° C. for 1.5 hrs and concentrated under reduced pressure. 5N Hydrochloric acid was added to acidify the solution (pH3) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgSO4). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with diisopropy ether to give the title compound (0.228 g) as a colorless powder with contamination.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cc(F)cc(F)c2)cc1-c1c(Br)cnn1C
Yield: 81.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 3,5-difluorophenyl isocyanate (0.018 g, 14 μL, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 7 (0.038 g, 0.09 mmol, 77%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.23 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.18-7.27 (m, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.59 (ttt, J=2.3, 9.1, 9.1 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [CH3:1][Mg]I.N[C:5]1[C:14]2[N:15]=[C:16]([CH2:27][CH2:28][CH2:29][CH3:30])[N:17](CCCC(N(OC)C)=O)[C:13]=2[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1.[O:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH2:27]([C:16]1[N:15]([CH2:35][CH2:34][CH2:33][C:32](=[O:31])[CH3:1])[C:14]2[C:5]3[N:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:11]=[CH:12][C:13]=2[N:17]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N(C)OC
Reactant: C[Mg]I
Reactant: C1CCOC1
Product: CCCCc1nc2cnc3cccnc3c2n1CCCC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methylmagnesium iodide (3M solution in tetrahydrofuran, 5.6 mL, 16.9 mmol, 1.5 eq) was added dropwise over 10 minutes to a chilled (0°) solution of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-N-methoxy-N-methylbutanamide (4.0 g, 11.25 mmol, 1 eq) in tetrahydrofuran (THF) (50 mL). The reaction mixture was stirred at ambient temperature for 4 hours, quenched with 1 M hydrochloric acid, and concentrated under reduced pressure. The residue was diluted with dichloromethane (75 mL) and saturated aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with dichloromethane (2×30 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to produce 3.12 g of 5-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one as a tan solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:25]1([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C)C(N(C)C)=N>CS(C)=O.O>[OH:33][CH2:32][CH:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)[CH3:34]
Reactant: CC(CO)N1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)CO)CC4)n3)nc2c1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
A mixture of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.202 g, 0.67 mmol), 2-(piperazin-1-yl)propan-1-ol dihydrochloride (0.292 g, 1.34 mmol) and 1,1,3,3-tetramethylguanidine (0.310 g, 2.69 mmol) in dry DMSO (1.5 mL) was heated at 85° C. for 6 h. After that time the reaction was cooled to rt, diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(6-(4-(1-hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.155 g, 54%) as a yellow solid: mp 202-204° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.87 (d, J=7.42 Hz, 1H), 7.64-7.72 (m, 1H), 6.79-6.88 (m, 2H) 6.49 (d, J=2.34 Hz, 1H) 3.99 (s, 3H), 3.94 (s, 3H), 3.61-3.72 (m, 4H), 3.38-3.52 (m, 2H), 2.89-2.99 (m, 1H), 2.78-2.88 (m, 2H), 2.54-2.64 (m, 2H), 0.97 (d, J=6.64 Hz, 3H); ESI MS m/z 426 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1)(=[O:7])=[O:6]
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)CCCCl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
3-Chloropropanesulfonyl chloride (1.0 g, 5.6 mmol) dissolved in CH2Cl2 (20 mL) and cooled to ˜0° C. was treated dropwise with a solution of 1-methylpiperazine (566 mg, 5.6 mmol) and Et3N (572 mg, 5.6 mmol) in CH2Cl2 (10 mL). Following complete addition, the mixture was allowed to warm to rt and stir an additional 2 h. The solvent was evaporated under reduced pressure, the residue triturated with EtOAc (30 mL), vacuum filtered and the solid washed well with EtOAc. The filtrate was concentrated under reduced pressure and the oil residue dried under high vacuum to give the title compound (1.27 g, 93%): 1H NMR (CDCl3) δ: 2.17-2.26 (2H, m), 2.49 (3H, s), 2.75-2.77 (4H, m), 3.02-3.07 (2H, m), 3.46-3.49 (4H, m), 3.60 (2H, t).
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH:12]=2)[C:5]1=[O:29])([CH3:3])[CH3:2].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=2)[CH:33]=1>>[ClH:30].[ClH:30].[ClH:30].[CH:1]([C@H:4]1[N:9]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=3)[CH:33]=2)[CH2:8][CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)[CH:12]=2)[C:5]1=[O:29])([CH3:3])[CH3:2].[ClH:30]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCN[C@H](C(C)C)C3=O)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)[C@H](C(C)C)C3=O)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
(3R)-3-Isopropyl-2-oxo-1-[[2-(3,4,5-trimethoxy-phenyl)pyridin-4-yl]methyl]piperazine (109 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (104 mg) were reacted in the same manner as in Example 4 to obtain the title compound as a hydrochloride.