Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C@:6]3([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[C:18]1(B(O)O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]1([C:2]2[CH:17]=[CH:16][C:5]3[C@:6]4([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=3[CH:3]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]4)[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Yield: 69.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (500 mg, 1.70 mmol), tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol), 1-napthylboronic acid (439 mg, 2.55 mmol), 2.4 mL of 2M sodium carbonate and 4 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (200 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (0-50% methanol/ethyl acetate eluent gradient) to give 405 mg (70%) of the title compound as a white solid. mp 247°-248°. FDMS: m/e=341. α[D]589 =+1.93 (c=1.04, methanol).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[NH2:10][C:4]1[N:3]=[C:2]([NH:14][CH2:13][CH2:11][OH:12])[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=1
Reactant: NCCO
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(NCCO)n1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 69.3 %

Procedure:
A mixture of 4,6-dichloropyrimidine-2,5-diamine (28 g, 156 mmol), ethanolamine (18 ml, 312 mmol) and ethanol (250 ml) were heated at 100-110° C. for 16 hours. The mixture was cooled and solvent was removed. To the residue methanol (100 ml) was added and stirred for 20 minutes. The solid was filtered off to obtain 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol (22.0 g, 70%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:22])([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)[CH:14]=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([C:4]2[C:5]([O:23][CH2:24][C:25]([F:26])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:16]3[N:20]=[C:19]([CH3:21])[O:18][N:17]=3)([CH3:22])[CH2:14][N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc(C(C)(C=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Reactant: FC1(F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(C)(CN2CC(F)(F)C2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.3 %

Procedure:
To a solution of 5-cyclopropyl-N-[1-methyl-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2-oxo-ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 128a, 0.075 g, 188 μmol) in dichloromethane (1 ml) was added 3,3-difluoroazetidine hydrochloride (26.8 mg, 207 μmol) and triethylamine (21.0 mg, 28.9 μl, 207 μmol). The reaction mixture was sonicated to completely dissolve solids and reaction mixture was then stirred at room temperature for 30 minutes, followed by addition of sodium triacetoxyborohydride (59.9 mg, 282 μmol). The reaction mixture was then stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with a 2M aqueous solution of sodium carbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (9.2 mg, 10%). MS (ESI, m/z): 476.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@@H:17]([O:28]S(C)(=O)=O)[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7].[CH2:35](O)[CH2:36][OH:37].N1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:35][CH2:36][OH:37])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: OCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 120 °C
Yield: 37 %

Procedure:
A pressure vessel (250 mL flask) containing the compound of Example 1A (10.0 g, 20 mmol) was charged with ethylene glycol (20 mL) and pyridine (4 mL) at ambient temperature, sealed and then heated at 120° C. for 4 hours. The reaction was cooled to ambient temperature, diluted with EtOAc (50 mL), and quenched with 1N HCl (30 mL). The layers were separated and the organic layer was washed with 1N HCl (2×30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%—>40% acetone/hexanes) provided the title compound (3.5 g, 37%). MS (ESI) m/e 484 (M+NH4)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(=O)(=O)CCCCl)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (78 mg, 0.19 mmol) and TEA (0.52 mL, 3.78 mmol) in DCM (10 mL) was added 3-chloropropane-1-sulfonyl chloride (63 mg, 0.36 mmol, in 1 mL DCM). After stirring at rt for one hour, EtOAc (100 mL) was added. The mixture was sequentially washed with water (10 mL), brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-100% EtOAc in hexanes gradient) to give 5-chloro-N2-(4-(1-(3-chloropropylsulfonyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as an off white solid; ESMS m/z 552.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH2:12])=[N:7][CH:6]=[CH:5]2.[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][CH:21]1[C:22](=[O:23])[NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Nc1nccc2cc(Br)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1nccc2cc(Br)ccc12
Reaction time: 6 h
Yield: 115.4 %

Procedure:
To a mixture of 6-Bromo-isoquinolin-1-ylamine (0.80 g), Boc-L-proline (0.803 g), and 4-methylmorpholine (0.83 mL) in DMF (10 mL) was added HATU (1.39 g). Reaction mixture was stirred for 6 hours. Additional Boc-L-proline (0.803 g), 4-methylmorpholine (0.83 mL) and HATU (1.39 g) were added and reaction stirred overnight at ambient temperature and then concentrated. The residue was dissolved in ethyl acetate and washed with 10:1 H2O/saturated sodium bicarbonate solution, 5% lithium chloride solution, brine and dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 70% ethyl acetate/hexanes) to give 2-(6-Bromo-isoquinolin-1-yl carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.74 g): LCMS-ESI+: calc'd for C19H23BrN3O3: 421.31 (M+H+). Found: 419.8, 421.8 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].C([O-])(O)=O.[Na+].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[C:32](Cl)=[O:33]>CC(C)=O>[CH3:41][O:40][C:36]1[CH:35]=[C:31]([CH:30]=[C:29]([O:28][CH3:27])[C:37]=1[O:38][CH3:39])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6])=[O:33]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1cc(C(=O)c2ccccc2)ccc1N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)Nc2cc(C(=O)c3ccccc3)ccc2N2CCOCC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
28 g. of 3-amino-4-morpholino-benzophenone are dissolved in 560 ml. of acetone, and 17 g. of solid sodium hydrocarbonate are added. A solution of 25.4 g. of 3,4,5-trimethoxybenzoyl chloride in 260 ml. of acetone are added dropwise to the solution at room temperature, under vigorous stirring. The temperature of the reaction mixture rises with about 6° to 10° C. After the addition the mixture is stirred for additional 30 minutes at room temperature, then poured into ice water. The separated product is filtered off, washed with water, dried, and crystallized from a mixture of acetone and ether. 37.5 g. of 3-(3,4,5-trimethoxybenzoylamino)-4-morpholino-benzophenone are obtained; m.p.: 171°-172° C.
Reaction SMILES: Cl.[OH2:2].N=[C:4]1[C:8]([CH3:15])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6](=[S:16])[N:5]1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:15][C:8]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6](=[S:16])[N:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]1=[O:2]
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=N
Reactant: O
Agent: Cl
Solvent: CO
Product: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
37% hydrochloric acid (5 ml) and water (1 ml) was added at room temperature with stirring to a solution of 4-imino-5-methyl-5-phenyl-3-phenylaminothiazolidine-2-thione (9.38 g) in methanol (50 ml). The solution was stirred for 24 hrs at room temperature. The solvent was then evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate-n-hexane, 1/3) to yield an oily 5-methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (7.02 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH2:37][OH:38])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-aminoethanol using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.42 (1H, b), 8.53 (1H, s), 8.25 (1H, s), 7.21-7.26 (2H, m), 6.97 (2H, t, J=8 Hz), 4.38 (2H, t, J=7 Hz), 4.15 (2H, s), 3.86 (2H, t, J=5 Hz), 3.49-3.66 (4H, m), 3.35 (2H, b), 2.85 (1H, t, J=5 Hz), 2.35 (2H, b), 1.72-1.76 (4H, m); ES+ MS: 483 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16](OCC)=[O:17])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.O>C1COCC1>[OH:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:14]=1
Reactant: CCOC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CCO)ccn1
Temperature: -69 °C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 2-(2-(tert-butoxycarbonylamino)pyridin-4-yl)acetate (19) (WO 2007089512) (10.0 g, 35.7 mmol) under nitrogen in THF (100 mL), at −78° C., was added DIBAL (1M solution in THF, 71.3 mL, 71.3 mmol) over 1 hr. The reaction mixture was stirred at −78 to −60° C. for 40 min and then warmed to −15° C. over 1 hr. The solution was re-cooled to −78° C. and treated with further DIBAL (1M solution in THF, 35 mL, 35.7 mmol). The mixture was allowed to warm to −40° C. and stirred for 1 hr. Water (10 mL) was added cautiously to quench the reaction followed by MgSO4 (20 g) and the solids removed by filtration. The filtrate was evaporated to dryness in vacuo and the residue subjected to column chromatography (SiO2, 330 g, 65% EtOAc in hexanes) to give the title compound (20) (6.00 g, 64%) as a yellow solid: m/z 239 (M+H)+ (ES+).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:11]([CH3:12])[C:6]2=[N:5][CH:4]=1)#[CH:2].[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36](Br)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])[CH3:26]>>[OH:23][CH2:24][C:25]([NH:28][S:29]([C:32]1[CH:33]=[N:34][CH:35]=[C:36]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=4)[CH:10]=[C:11]([CH3:12])[C:6]3=[N:5][CH:4]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cncc(S(=O)(=O)NC(C)(C)CO)c3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.20) (300 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (278 mg, 0.9 mmol) according to general procedure II. Obtained as a white solid (60 mg, 11%). MS (ISP) 529.1 [(M+H)+]; mp 189° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18](O)=O)=[CH:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]([NH:52][C:53]1[C:58]([NH2:59])=[CH:57][CH:56]=[C:55]([N:60]2[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]2)[N:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH2:45]([N:52]1[C:53]2=[N:54][C:55]([N:60]3[CH2:61][CH2:62][N:63]([CH3:66])[CH2:64][CH2:65]3)=[CH:56][CH:57]=[C:58]2[N:59]=[C:18]1[C:13]1[CH:14]=[CH:15][C:16](=[O:17])[N:11]([CH3:10])[CH:12]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Cn1cc(C(=O)O)ccc1=O
Reactant: CN1CCN(c2ccc(N)c(NCc3ccccc3)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3nc(-c4ccc(=O)n(C)c4)n(Cc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DIPEA (51 mg; 0.392 mmol) is added to a suspension of 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D-7 (20 mg; 0.131 mmol) and HATU (70 mg; 0.183 mg) in DMF. The mixture is stirred at RT for 5 min. N2-Benzyl-6-(4-methyl-piperazin-1-yl)-pyridine-2,3-diamine E-3.1 is then added and the reaction mixture stirred at RT for 1 h. The reaction mixture is extracted with DCM and NaHCO3 solution. The organic layer is dried over Na2SO4 and concentrated in vacuum. To the formed amide is added 1 ml glacial acetic acid, the reaction is stirred at 120° C. for 2 days. The crude reaction mixture is purified by using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: Cl.Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.Cl[C:31]1[N:36]=[C:35]([C:37]2[S:41][C:40]3[C:42]([O:46][CH3:47])=[CH:43][CH:44]=[CH:45][C:39]=3[CH:38]=2)[C:34]([Cl:48])=[CH:33][N:32]=1.NCCCN1CCN(C)CC1>>[Cl:48][C:34]1[C:35]([C:37]2[S:41][C:40]3[C:42]([O:46][CH3:47])=[CH:43][CH:44]=[CH:45][C:39]=3[CH:38]=2)=[N:36][C:31]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)=[N:32][CH:33]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Reactant: COc1cccc2cc(-c3nc(Cl)ncc3Cl)sc12
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: COc1cccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc12

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 2,5-dichloro-4-(7-methoxybenzo[b]thiophen-2-yl)-pyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a yellowish solid. ES+(m/z) 432(35Cl) and 434(37Cl) [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[F:8].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1F)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 15.1 g (58.1 mmol) of 3-chloro-2,4-difluoro(trifluoroacetamido)benzene in 80 mL of H2SO4 kept in an ice-bath was added dropwise 10 mL of HNO3. Solid precipitate was observed during addition of HNO3. The mixture was stirred in an ice-bath for 4 h. It was added into 600 mL of ice-water. The precipitate was filtered and washed by water, and dried to leave almost colorless solid (16.8 g, 95%), mp 124°-125° C. 1H NMR (CDCl3), 7.69 (dd, 1), 8.936 (mb, 1).
Reaction SMILES: C[C:2]1C=C[C:5]([CH:8](C)[C:9]([NH2:11])=O)=[CH:4][CH:3]=1.[Li].O.[OH-].[Na+].O1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:18][C:19]1[CH:2]=[CH:3][C:4]([CH2:5][CH2:8][CH2:9][NH2:11])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(C)C(N)=O)cc1
Reactant: C1CCOC1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CCCN)cc1

Procedure:
2-(4-Methylphenyl)propionamide (4 g) in dry tetrahydrofuran was added dropwise under nitrogen to lithium alumimium hydride (0.93 g) in dry tetrahydrofuran. The mixture was refluxed for 1 h at the end of addition. Water (1 ml), 2N. NaOH (1 ml), further water (3 ml) were added, the mixture filtered and the filtrate evaporated to give 3-(4-methylphenyl)propanamine (3.5 g).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11]C)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=C(C=CC=2)C(O)=O)C=CN=C1.[C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:32])[CH3:31].[Li]>OS(O)(=O)=O.CO>[C:34]([O:33][C:30](=[O:32])[CH2:31][C:9]([C:8]1[CH:13]=[CH:14][CH:15]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=1)=[O:11])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(-n2ccnc2)c1
Agent: O=C(O)c1cccc(-n2ccnc2)c1
Agent: O=S(=O)(O)O
Agent: [Li]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
Prepared from methyl 3-(1H-imidazol-1-yl)benzoate [prepared from 3-(1H-imidazol-1-yl)benzoic acid (J. Med. Chem. 1987, 30, 1342; CAS-No. [108035-47-8] by refluxing in conc. H2SO4/MeOH] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as an orange-brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:30]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:30]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.5 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (300 mg, 0.727 mmol) in N,N-dimethylacetamide (3.0 mL) was added cyclopropanecarbonyl chloride (69 μL, 0.763 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (200 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=60/40→0/100), and fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with ethyl acetate, diisopropyl ether and hexane to give the title compound (145 mg, 42%) as a colorless solid.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:12][CH:13]=1)([O-:7])=[O:6].[CH3:21][C:22]([CH3:24])=O.C([BH3-])#N.[Na+]>CO>[CH:22]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][N:12]=2)[CH2:16][CH2:17]1)([CH3:24])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)nc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10% acetic acid in methanol was added 5-nitro-2-(piperidin-4-yloxy)pyridine (1 eq) and anhydrous acetone (5 eq). The solution was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C. on an ice bath and sodium cyanoborohydride (1.5 eq) was added. The reaction mixture was then warmed to room temperature and stirred for 5 hours. The solvent was evaporated, the residue brought to pH=10 with sodium carbonate and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, and evaporated to give the crude material. Purification by silica gel column chromatography using 2% methanol/dichloromethane afforded the product as a yellow solid. LC/MS (m/z): 266.3 (MH+), Rt 1.85 minutes.