Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[K].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=1[OH:25]>CS(C)=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:25][C:18]2[C:17]([Cl:16])=[CH:22][C:21]([Cl:23])=[CH:20][C:19]=2[Cl:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([O-:14])=[O:13]
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A stirred solution of methyl 5-chloro-2-nitro-benzoate (17.0 g., 0.079 mole) and the potassium salt of 2,4,6-trichlorophenol (18.6 g., 0.079 mole) in dimethyl sulfoxide (100 ml.) was heated at 90° C. for 17 hours. The cooled reaction mixture was diluted with water (500 ml.) and then extracted with ether (3×100 ml.). The combined ether fractions were washed with 10% sodium hydroxide solution (2×30 ml.) and then with a saturated aqueous sodium chloride solution. The ether solution was dried (Na2SO4) and the solvent evaporated to give a dark oil. Two crystallizations (petroleum ether) gave 1.91 g. of a pale yellow solid, m.p. 101°-103° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]2)=[CH:5][C:4]=1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)#[N:2].[OH-:38].[Na+].OO>CO.CS(C)=O.C(#N)C.CCOC(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10]2)=[CH:5][C:4]=1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])=[CH:26][CH:25]=1)(=[O:38])[NH2:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(C(=O)N4CCOCC4)cc3)c2)C1
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)c2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a solution of (R)-tert-butyl 1-(6-cyano-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate (96) in MeOH (15 mL) and DMSO (1.5 mL) was added solid NaOH (100 mg) and 30% H2O2 (1.5 mL). The mixture was stirred at RT for 20 min, diluted with acetonitrile (5 mL), and EtOAc (200 mL) 10 min later. The organic phase was washed with water ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 5% MeOH in DCM to give (R)-tert-butyl 1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate (97) (yield >90%). (R)-tert-butyl 1-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)pyridin-3-yl)piperidin-3-ylcarbamate (97) was treated with 4N HCl in dioxane (30 mL) for 30 min. The mixture was concentrated in vacuo to dryness to afford (R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)picolinamide, HCl salt (98).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[CH3:15][C:16]([CH3:46])([CH3:45])[CH2:17][N:18]([CH3:44])[C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]=[C:21]([NH:29][C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:33]([NH:35][CH3:36])=[O:34])[C:20]=1[N+:41]([O-:43])=[O:42]>CS(C)=O>[CH3:15][C:16]([CH3:46])([CH3:45])[CH2:17][N:18]([CH3:44])[C:19]1[N:24]=[C:23]([O:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:22]=[C:21]([NH:29][C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][C:39]=2[CH3:40])[C:33]([NH:35][CH3:36])=[O:34])[C:20]=1[N+:41]([O-:43])=[O:42]
Reactant: CN1CCC(O)CC1
Reactant: CNC(=O)c1ccc(C)c(Nc2nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(C)c(Nc2nc(OC3CCN(C)CC3)nc(N(C)CC(C)(C)C)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
1-Methyl-piperidin-4-ol (56 mg, 0.5 mmol) was dissolved in 2 mL of DMSO. To the solution was added potassium tert-butoxide (56 mg, 0.5 mmol). The solution was stirred at room temperature for 1 h. The solution was then added to a solution of 3-{6-[(2,2-Dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-5-nitro-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (4 mg, 0.01 mmol) in 0.5 mL of DMSO. The solution was stirred at 80° C. for 3 h, and extracted with ethyl acetate and water. The organic layer was washed with water, brine, dried over MgSO4, and evaporated under vacuum. The residue was purified by semi-preparative hplc column to afford 0.7 mg of the product (Yield: 16%). MS (m/z) calcd for C25H37N7O4 (MH+), 500.2, found, 500.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]([N+:15]([O-])=O)[CH:4]=[N:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.C(Cl)Cl.[Pd].O>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:15][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[O:7][CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:28]=1
Reactant: Cn1ncc([N+](=O)[O-])c1OCC1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A solution of 1-methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole (0.143 g, 0.59 mmol) in MeOH (15 mL) was passed through the H-Cube® (70 bar, 60° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford the crude amine as a brown oil (0.115 g, 0.54 mmol). To a solution of this amine in DCM (8 mL) was added 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.206 g, 0.58 mmol), HATU (0.615 g, 1.62 mmol) and DIPEA (0.66 mL, 3.78 mmol). The mixture was stirred at room temperature for 18 hr. Water (30 ml) was added and stirring continued for 15 min. The layers were separated and the aqueous extracted with DCM. The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a yellow solid (0.22 g, 69%). This solid (0.129 g, 0.25 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 4 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 0.3 M ammonia in MeOH to yield a coloured foam. Further purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 230 as a white solid (70 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.62 (s, 1H), 7.37-7.28 (m, 1H), 7.07-6.97 (m, 2H), 6.15 (s, 2H), 4.02 (d, J=6.5 Hz, 2H), 3.96 (dd, J=11.5, 4.5 Hz, 2H), 3.69 (s, 3H), 3.43-3.35 (m, 2H), 2.11-1.98 (m, 1H), 1.75-1.69 (m, 2H), 1.51-1.38 (m, 2H). LCMS (ES+) m/z 450 (M+1)
Reaction SMILES: [CH3:1][N:2]([CH:17]1[CH2:27][CH2:26][C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18]1)[C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:4]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:1][N:2]([C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:4]=1)[CH:17]1[CH2:27][CH2:26][C:20]2([CH2:25][CH2:24][N:23]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:22][CH2:21]2)[CH2:19][CH2:18]1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a suspension of N4,5-dimethyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (93 mg, 0.25 mmol) and 2-cyanoacetic acid (63.8 mg, 0.75 mmol) in a mixture of dichloromethane and N,N-dimethylformamide (8 mL/2 mL) were added O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro phosphate (51.72 mg, 0.38 mmol) and N,N-diethylethanamine (75.9 mg, 0.75 mmol). The mixture was stirred at rt overnight then concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a yellow solid (40 mg, 36.38%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](Br)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(C#C[Si](C)(C)C)c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Yield: 45.1 %

Procedure:
3-Bromo 5-nitro-indazole-1-carboxylic acid tert-butyl ester (2 g, 5.8 mmol) was dissolved in dry DMF (30 mL) under nitrogen and triethylamine (1.6 mL, 1.6 mmol) added. Copper iodide (20 mg, 0.12 mmol), trimethylsilylacetylene (2.5 mL, 17.4 mmol) palladium bis-triphenylphosphine dichloride (84 mg, 0.12 mmol) and a further 1.6 mL of triethylamine were added and the mixture heated at 50° C. overnight. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was taken up in EtOAc and filtered through a plug of Celite®. The filtrate was washed with saturated ammonium chloride solution and dried over sodium sulfate then concentrated to a black foam. Purification by chromatography (silica, 1:1 petrol-EtOAc) gave the title compound as a black solid (940 mg, 45%); MS (ES+) m/e=360.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([OH:9])[CH3:8].Cl[C:11]1[CH:16]=[C:15]([C:17]2[N:21]3[CH:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O.O>[CH2:7]([O:9][C:13]1[CH:14]=[C:15]([C:17]2[N:21]3[CH:22]=[C:23]([NH:26][CH:27]4[CH2:28][CH2:29][CH:30]([OH:33])[CH2:31][CH2:32]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:16]=[CH:11][N:12]=1)[CH3:8]
Reactant: CCO
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(-c2cnc3ccc(NC4CCC(O)CC4)cn23)ccn1
Temperature: 120 °C

Procedure:
Cs2CO3 (5 eq, 1.45 mmol, 480 mg) and 4A molecular sieves (400 mg) are stirred in a mixture of DMSO (5 ml) and ethanol (5 eq 0.8 ml). To this suspension is added [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 100 mg, 0.29 mmol). The reaction is heated at 120° C. for 16 hours. The mixture is diluted with H2O (20 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo to give a blue oil. The residue is purified by flash chromatography on silica eluting with 0-10% methanol in EtOAc The resulting residue is loaded onto a SCX-2 cartridge (resin loading 0.67 mmol/g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+=353
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:35](I)[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:35]([O:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])=[CH:3][C:2]=1[F:1])[CH3:36]
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and ethyl iodide (0.53 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.44 g), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.96 g, 91%).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([Cl:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:9]1[C:8]2[C:7](=[O:21])[C:6]3[CH:5]=[C:4]4[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]4=[C:16]([Cl:19])[C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C=CCc1cc2c(=O)c3c(Cl)cccc3oc2c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C1Cc2cc3c(=O)c4c(Cl)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
A mixture of 2-allyl-4,8-dichloro-3-hydroxy-9-oxo-9H-xanthene (14 g), m-chloroperbenzoic acid (11 g ) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (2,000 ml) and to the stirred solution, a mixture of chromium trioxide (17 g), water (100 ml) and concentrated sulfuric acid (30 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 5.0 g of 6,11-dichloro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 291°-294° C. This compound showed a mass spectrum having a molecular ion peak at m/e 350.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C.CS(C)=O>O>[Br:8][C:6]1[N:7]=[C:2]([NH:19][CH:16]([CH3:18])[CH3:17])[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CC(C)N
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)CNc1ncc(Br)nc1NC(C)C
Temperature: 150 °C
Yield: 55.5 %

Procedure:
A mixture of ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (See Example 6.B) (1.5 g, 4.43 mmol), isopropylamine (0.17 g, 4.87 mmol), N,N-diisopropylethylamine (1.14 g, 8.84 mmol) and dimethylsulfoxide (10 mL) in a reaction vial was heated in an oil bath at 150° C. for 16 h. After being cooled to room temperature, the resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, evaporated under reduced pressure and purified on silica gel column chromatography (10-20% ethyl acetate in petroleum ether) to give the title compound (780 mg, 55.7% yield). MS (ESI) m/z 316.9 [M+1]+.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10](=[O:41])[C:11]([NH:32][NH:33]C(OC(C)(C)C)=O)([CH3:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([O:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.Cl>C(Cl)Cl.O1CCOCC1>[C:6]([CH2:8][O:9][C:10](=[O:41])[C:11]([NH:32][NH2:33])([CH3:31])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([O:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)Oc1ccc(CC(C)(NNC(=O)OC(C)(C)C)C(=O)OCC(=O)OC(C)(C)C)cc1OC(=O)OCC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCC(=O)O)cc1OC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 155 was dissolved in 2 mL CH2Cl2 and treated with 1 mL trifluoroacetic acid at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0° C. again and a solution (1 mL) of 4 N HCl in dioxane was added. After stirring at room temperature for 2 h, the solvent was removed in vacuo. The crude residue was purified by reverse phase LC/MS to afford 103 mg (24% overall yield) of the title compound. 1H-NMR (400 MHz, CD3OD): δ 7.14–7.22 (m, 3H), 4.49–4.69 (Abq, J=62.8, 14.8, 2H), 4.24–4.29 (m, 4H), 3.03–3.13 (q, J=13.6 Hz), 1.33 (t, J=6.0 Hz, 6H). MS (ESI) m/z 429.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:12][C:11]([Cl:13])=[N:10][C:9]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[S:12][C:11]([Cl:13])=[N:10][C:9]=1[Cl:14])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1sc(Cl)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CSCCC(=O)N(C(=O)OC(C)(C)C)c1sc(Cl)nc1Cl
Temperature: 75 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of (2,4-dichloro-thiazol-5-yl)-carbamic acid tert-butyl ester (1.0 g, 3.7 mmol) in dichloroethane (20 mL) stirring at room temperature was added triethylamine (935 mg, 9.25 mmol), followed by dropwise addition of methylsulfanyl-propionyl chloride (776 mg, 5.6 mmol) and the mixture was stirred for 5 min before DMAP (45 mg, 0.37 mmol) was added. The mixture was stirred at 75° C. for 4 h. The reaction mixture was cooled, quenched with H2O (30 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (20 mL). The combined organic layer was dried over Na2SO4 and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a colorless oil (1.11 g, 81%): 1H NMR (300 MHz, CDCl3) δ 3.32 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 2.16 (s, 3H), 1.46 (s, 9H); ESIMS m/z 371.2 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[O:13])[CH2:11]Br)[N:9]=1)(=[O:3])[CH3:2].O[CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl.CO>[C:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([N:17]2[CH2:16][CH2:15][O:13][CH:10]([C:8]3[N:9]=[C:5]([NH:4][C:1]([CH3:2])=[O:3])[S:6][CH:7]=3)[CH2:11]2)[CH3:32])=[CH:21][CH:22]=1)([O:30][CH3:31])=[O:29]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: CC(=O)Nc1nc(C(=O)CBr)cs1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(NC(C)=O)n3)C2)cc1

Procedure:
Prepared by analogy to Example 32 by reaction of 2.23 g (0.0085 mol) of 2-acetylamino-4-bromoacetylthiazole with 2.26 g of (0.0085 mol) of N-(2-hydroxy-ethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine and 0.86 g (0.0085 mol) of triethylamine in 30 ml of methylene chloride and 30 ml of methanol for 20 hours at room temperature. The reduction is carried out in 9 ml of trifluoroacetic acid using 1.48 g (0.0128 mol) of triethylsilane. The crude product is purified on a silica gel column using ethyl acetate/methanol=9:1 as eluant.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][CH2:18][OH:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23](S(O)(=O)=O)=[CH:22][CH:21]=1>C(O)C1C=CC=CC=1>[CH2:30]([O:19][CH2:18][NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCNc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Product: Fc1ccc(COc2ncc(F)c(NCOCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methanol (0.10 g, 3.7 mmol) in benzyl alcohol (1 mL) was added a catalytic amount of p-toluene sulfonic acid. After 30 min, the reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic portion was dried over anhydrous Na2SO4, filtered and evaporated to obtain the crude product. Purification by reverse phase chromatography afforded 0.094 g (70%) of the title compound as a white solid: mp 64-66° C.; 1H NMR (CDCl3) δ 7.93 (d, J=2.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.37-7.29 (m, 5H), 7.08-7.00 (m, 2H), 5.81-5.70 (bm, 1H), 5.29 (s, 2H), 5.12 (d, J=6.9 Hz, 2H), 4.63 (s, 2H); MS (ESI) m/z 358 (M+H)+.
Reaction SMILES: ClC(Cl)C.[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10](=[O:29])[N:11]([CH2:27][CH3:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[CH:16][CH:15]=[C:14]([CH3:26])[N:13]=2.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[N:13][C:14]([CH3:26])=[CH:15][CH:16]=3)[N:11]([CH2:27][CH3:28])[C:10](=[O:29])[C:9]=2[CH2:8][CH2:7][CH2:6][NH:5][S:31]([CH3:30])(=[O:33])=[O:32])[CH:24]=[CH:23][CH:22]=1
Reactant: CCn1c(=O)c(CCCN)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCn1c(=O)c(CCCNS(C)(=O)=O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a 10 ml dichloroethane solution containing 630 mg of 3-(3-aminopropyl)-4-(3-chlorophenyl)-l-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one were added 243 mg of methanesulfonyl chloride and 0.30 ml of triethylamine under ice cooling, followed by stirring for 1 hour with warming to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate aqueous solution and saturated brine. The solvent was evaporated from the organic layer and the resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethanol-water to obtain 204 mg of N-{3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propyl}methanesulfonamide as colorless crystals.