Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([Cl:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.CCN(C(C)C)C(C)C.[CH3:53][C:54]1[C:58]([C:59](O)=[O:60])=[C:57]([CH3:62])[O:56][N:55]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:59]([C:58]1[C:54]([CH3:53])=[N:55][O:56][C:57]=1[CH3:62])=[O:60]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3Cl)ccc21
Reactant: Cc1noc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1C(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To a solution of 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 218, 0.05 g, 0.148 mmol) in dry DMF (1 mL) were added EDCI (0.034 g, 0.077 mmol), hydroxybenzotriazole (0.017 g, 0.077 mmol), Hünig's base (0.057 g, 0.443 mmol) and 3,5-dimethyl-isoxazole-4-carboxylic acid (0.021 g, 0.148 mmol) and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (10 mL) and extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.03 g, 48%) as a colorless solid. MS: 425.4 (M+H+).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[S:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[OH:21][C:7]1[C:8]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: CCOC(=O)c1ncc2sc(-c3ccccc3)nc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2sc(-c3ccccc3)nc2c1O
Temperature: 120 °C
Yield: 75.9 %

Procedure:
A mixture of 7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (31 mg, 0.10 mmol) and glycine (78 mg, 1.04 mmol) in 0.5 M sodium methoxide/methanol (1.7 mL) was heated at 120° C. using a CEM microwave reactor for 30 min before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (18 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (1.2 mL). The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (25 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.30 (br s, 1H), 9.42 (t, 1H), 8.96 (s, 1H), 8.14 (m, 2H), 7.67 (m, 3H), 4.02 (d, J=6.2 Hz, 2H); MS: (+) m/z 330.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:24]([O:26][CH3:27])=[O:25])=[C:14](OS(C(F)(F)F)(=O)=O)[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1B(O)O)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC>[CH2:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:14]1[N:15]=[C:11]([C:10]2[C:2]([CH3:1])=[N:3][N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=23)[S:12][C:13]=1[C:24]([O:26][CH3:27])=[O:25])[CH3:29]
Reactant: CCOc1cccc(F)c1B(O)O
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOc1cccc(F)c1-c1nc(-c2c(C)nn3ccccc23)sc1C(=O)OC
Temperature: 90 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
A suspension of Methyl 2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1,3-thiazole-5-carboxylate (306 mg, 0.72 mmol) obtained in Example 13-B(ii), (2-ethoxy-6-fluorophenyl)boronic acid (262 mg, 1.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (80 mg, 0.098 mmol) and cesium carbonate (850 mg, 2.6 mmol) in DME (20 mL), was added water (2 mL), and the mixture was stirred at 90° C. for 5 h. The reaction mixture was allowed to cool to rt, water (200 mL) was added, and the mixture was extracted with EtOAc (100 mL×2). The combined organic layers were dried over anhydrous magnesium sulfate, insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=50/50→100/0) to give the title compound (295 mg, 100%) as a yellow solid. 1H-NMR (DMSO-d6, 300 MHz) δ 1.07-1.23 (3H, m), 2.70 (3H, s), 3.72 (3H, s), 3.97-4.13 (2H, m), 6.85-7.61 (5H, m), 8.29 (1H, d, J=8.9 Hz), 8.80 (1H, d, J=6.8 Hz).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)([Cl:68])=O>C(Cl)(Cl)Cl>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23][Cl:68])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 110.6 %

Procedure:
3,4,5-Tris(octadecyloxy)benzyl alcohol (83.0 g, 90.8 mmol) was dissolved in chloroform (830 ml), thionyl chloride (21.6 g, 0.182 mol) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated, and the residue was precipitated with acetonitrile (800 ml) to give 3,4,5-tri(octadecyloxy)benzylchloride (93.6 g) as wet crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:8]=[C:9]([S:11]([NH:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][C:33]([C:41]1[S:45][C:44]([NH2:46])=[N:43][N:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:17])=[C:4]([CH:8]=[C:9]([S:11]([NH:14][CH2:15][CH3:16])(=[O:13])=[O:12])[CH:10]=1)[C:5]([NH:46][C:44]1[S:45][C:41]([C:33]([CH3:34])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:32])=[N:42][N:43]=1)=[O:7]
Reactant: CC(C)(c1ccccc1)c1nnc(N)s1
Reactant: CCNS(=O)(=O)c1cc(Cl)c(F)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1cc(Cl)c(F)c(C(=O)Nc2nnc(C(C)(C)c3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.2 %

Procedure:
To 3-chloro-5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid (60 mg, 0.213 mmol) in DMF (3 ml) and DCM (3 ml) was added EDC (40.8 mg, 0.213 mmol) and HOBt (32.6 mg, 0.213 mmol). After 10 mins, 5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-amine (41.6 mg) was added. The reaction mixture was stirred at rt overnight, concentrated and purifed by HPLC to give the title compound (100 mg) LC/MS: m/z 482.8 (M+H), rt 2.05 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][N:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:35]
Reactant: CCOC(=O)CCCCCCBr
Reactant: c1ccc(COc2ccc(Nc3ccccn3)nc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OCc2ccccc2)cn1
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
NaH (48 mg, 1.26 6 mmol) was added to II (350 mg, 1.26 mmol) in DMF (6 mL) at rt. After 10 min, KI (314 mg, 1.89 mmol) and ethyl 7-bromoheptanoate (0.370 mL, 1.89 mmol) were added. The reaction mixture was stirred at 90° C. for 18 h30 after which 0.1 M Na2S2O3 (50 mL) and EtOAc (50 mL) were added, the phases were separated and the aqueous extracted with EtOAc (2×25 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (80:20 then 70:30) to furnish III as a colourless oil (308 mg, 56%).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19])#[N:2].C(O)C.O.[H][H]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[CH:5][C:4]=1[F:19]
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)NC2CCCCCC2)cc1F
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: NCc1ccc(C(=O)NC2CCCCCC2)cc1F
Reaction time: 0.5 h

Procedure:
Add 4-cyano-N-cycloheptyl-3-fluoro-benzamide (0.86 g, 3.3 mmol), 10% Pd/C (Degussa type E101, 250 mg), ethanol (25 mL), water (9 mL) and acetic acid (1 mL) to a pressure vessel under a nitrogen atmosphere. Pressurize the vessel to 50 psi with hydrogen, and stir the mixture for 0.5 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the title compound as the acetic acid salt. Use SCX chromatography to obtain the title compound (805 mg, 92%). MS (ES+) m/z: 265.3 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)(C)(C)C.[Cl:10][C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25]C)=[CH:22][CH:23]=3)[C:18]([S:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:17]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:13][CH:12]=1.Cl>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[C:18]([S:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[C:17]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)(C)S
Product: CCOC(=O)c1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 91.4 %

Procedure:
To a 0° C. suspension of anhydrous aluminum chloride (4.8 g, 36 mmol) in CH2Cl2 (15 ml) was added t-butyl mercaptan (12 ml) followed by ethyl 1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindole-2-carboxylate (3.77 g; 11 mmol), prepared as in step 2, and the resulting mixture was stirred at 0° C. for 45 min. The reaction mixture was then poured into ice and aqueous 1N hydrochloric acid (100 ml) and extracted with ethyl acetate. The organic phase was concentrated in vacuo to provide 4.2 g of crude oily ethyl 1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindole-2-carboxylate which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(#N)C.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:17]([C:21]([NH:23][CH2:24][C:25]3([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:22])=[C:16]([Cl:33])[CH:15]=[CH:14][C:13]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:21]([NH:23][CH2:24][C:25]4([OH:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:22])=[C:16]([Cl:33])[CH:15]=[CH:14][C:13]=3[N:12]=2)[CH2:3]1
Reactant: O=C(NCC1(O)CCCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reaction time: 1.58 h

Procedure:
(S)-3 aminopyrrolidine (96 ml) and acetonitrile (300 ml) were charged to a vessel containing 2,6-Dichloro-N-((1-hydroxycycloheptyl)methyl)quinoline-5-carboxamide (300.0 g), potassium carbonate (249.0 g) and acetonitrile (2400 ml). The reaction mixture was heated under refux for 20 hours. Water (6900 ml) was charged at 20° C. to 25° C. The mixture was stirred for 95 minutes and filtered. The filter cake was washed with water (1200 ml) and acetonitrile (1200 ml). The filter cake was dried at 40° C. for 48 hours to provide the title compound as a yellow solid (283 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C.C(OCC)C>[CH2:25]([O:24][C:18]1[CH:19]=[CH:20][C:21]([Br:23])=[CH:22][C:17]=1[CH2:16][CH2:15][N:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:13][N:12]=1)[CH2:35][CH3:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCI
Reactant: CC(C)(C)OC(=O)c1ccc(NCCc2cc(Br)ccc2OCc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN(CCc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl2-[N-(2-benzyloxy-5-bromophenethyl)-amino]-5-pyridinecarboxylate (850 mg), and sodium hydride (110 mg, 50% dispersion in oil) in DMF (20 ml) was stirred for 15 minutes then iodoethane (150 ml) was added and the mixture sitrred for 2 hours. The mixture was diluted with diethyl ether (50 ml) washed with water, dried (MgSO4), filtered through silica gel, evaporated and the residue re-dissolved in dichloromethane and evaporated to give tert-butyl 2-[N-(2-benzyloxy-5-bromophenethyl)-N-ethylamino]-5-pyridine carboxylate (800 mg).
Reaction SMILES: [S:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[C:34]([NH2:44])[CH:33]=1>O.C(Cl)CCl.CN(C=O)C>[CH3:29][O:30][C:31](=[O:45])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[C:34]([NH:44][C:7](=[O:9])[CH2:6][C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH:33]=1
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1N
Reactant: O=C(O)Cc1cncs1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cncs1
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a solution of 1.00 g of Thiazol-5-yl-acetic acid in 17 nil of dry DMF 0.48 g of HOAT, 1.61 g of EDC and 2.3 ml of DIPEA were added at 0° C. After 30 min 1.65 g of 3-Amino-4-(1-ethyl-propylamino)-benzoic acid methyl ester were added, followed by the addition of 2 ml of DIPEA and the reaction was stirred at it for 48 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 2.16 g (85%) of 4-(1-Ethyl-propylamino)-3-(2-thiazol-5-yl-acetylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:11])[O:9][CH3:10])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].CCN(C(C)C)C(C)C>C1COCC1>[CH3:10][O:9][N:8]([CH3:11])[C:6]1[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:1][C:16](=[O:19])[CH2:17][CH3:18])[N:7]=1
Reactant: CCCNc1nc(N)nc(N(C)OC)n1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(NC(=O)CC)nc(N(C)OC)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) (5 g, 23.58 mmol) was dissolved in THF (50 mL). Propionyl chloride (3.25 g, 35.38 mmol) and DIPEA (5.47 g, 42.44 mmol) were added at 0° C. The resultant mixture was stirred at ambient temperature for 10 min, then stirred at 70° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (250 mL), and this extract was washed with water (80 mL) and then with a brine solution (80 mL), and lastly dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (pet ether/ethyl acetate=5/1 to 2/1) to yield 930 mg (15%) of the desired product. The isolated free amine (930 mg, 3.47 mmol) was dissolved in H2O (10 mL) and 0.5 M HCl solution in H2O (10.4 mL) and then the solution was lyophilized to yield N-(4-(methoxy(methyl)amino)-6-(n-propylamino)-1,3,5-triazin-2-yl)propionamide (XL) as a colorless oil (1.06 g). LCMS: (ESI) m/z=269 (M+H)+. 1H NMR (500 MHz, DMSO): δ (ppm) 12.23 (s, 1H), 8.25-9.45 (m, 2H), 3.76-3.84 (m, 3H), 3.30-3.44 (m, 5H), 2.55-2.56 (m, 1H), 2.21-2.22 (m, 1H), 1.53-1.58 (m, 2H), 0.88-1.08 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([C:12]4[CH:21]=[N:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]=4)[CH:7]=3)=[O:4])[CH2:33][CH2:32]2)=[CH:29][CH:30]=1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(c2ccc(Cl)cc2)CC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 36.4 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), 1-(4-chlorophenyl)piperazine dihydrochloride (100 mg, 0.367 mmol) and K2CO3 (149 mg, 1.075 mmol) in MeCN (5 mL) was heated at reflux for 24 hrs. The reaction mixture was diluted with ethyl acetate (20 mL), and the organic phase washed with water (20 mL) and then brine (20 mL), dried over MgSO4 and evaporated in vacuo. The residue was triturated with diethyl ether and dried in vacuo at 50° C. to afford 2-[4-(4-chlorophenyl)piperazin-1-yl]-N-(3-(quinoxalin-2-yl)phenyl)acetamide (56 mg, 36% yield). LCMS calculated for C26H24ClN5O (M+H): 458.17. found 458.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.00 (1H, br. s), 9.51 (1H, s), 8.55 (1H, m), 8.15-8.10 (2H, m), 8.05 (1H, d, 1=7.5 Hz), 7.95-7.80 (3H, m), 7.55 (1H, m), 7.21 (2H, d, J=7.5 Hz), 6.90 (2H, d, J=7.5 Hz), 3.21 (4H, m), 2.61 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.C[Si](C)(C)[C:12]([F:15])([F:14])[F:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[C:12]([F:15])([F:14])[F:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a cooled (0° C.) solution of 5-bromo-pyridine-3-carbaldehyde (2.0 g, 10.8 mmol) in THF (25 mL) are added trimethyl-trifluoromethyl-silane (2.8 mL, 18.8 mmol) and TBAF in THF solution (1.0 M; 10.8 mL, 10.8 mmol). The mixture is warmed to room temperature for 3 hrs. The solvent is evaporated to give the crude product. Purification by flash column chromatography affords 1.9 g of 1-(5-bromo-pyridin-3-yl)-2,2,2-trifluoro-ethanol.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[C:8]([NH:13][C:14](=O)[CH2:15][CH2:16][O:17][CH3:18])[CH:9]=[N:10]2)=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O.C>C(Cl)(Cl)Cl.CO.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6]2[C:7]3[N:20]([CH2:21][C:22]([CH3:24])([OH:25])[CH3:23])[C:14]([CH2:15][CH2:16][O:17][CH3:18])=[N:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: COCCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COCCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Yield: 73.6 %

Procedure:
A mixture of N-{7-bromo-4-[(2-hydroxy-2-methylpropyl)amino][1,5]naphthyridin-3-yl}-3-methoxypropionamide hydrochloride (60.00 g, 138 mmol), potassium carbonate (60 g), water (300 mL), and ethanol (900 mL) was heated at reflux for 16 hours and then concentrated under reduced pressure. The precipitated solid was isolated by filtration, washed sequentially with water and methanol, and dried to provide a brown solid. This material was dissolved in a 3/1 mixture of chloroform/methanol and decolorized with activated charcoal to provide 38.5 g of 1-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a white solid, mp 125° C. Anal. calcd for C16H19BrN4O2: % C, 50.67; % H, 5.05; % N, 14.77. Found: % C, 50.86; % H, 4.94; % N, 15.01.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:35][CH:34]([CH3:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:33]4[CH:34]([CH3:36])[CH2:35][N:31]([CH2:30][C:29]5[CH:38]=[CH:39][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:37])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cn3)C2=O)cc1
Yield: 64.2 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) was obtained. The obtained 3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) was dissolved in trifluoroacetic acid (2 mL), trifluoromethanesulfonic acid (0.11 mL) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the solvent was evaporated, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (83 mg).