Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2C=CC=C[C:29]=2N=N1.C1CCN2C(=NCCC2)CC1.[O-]CC.[Na+]>CCO>[CH2:29]([O:18][C:4]1[C:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1)[CH3:30]
Reactant: Nc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)nc2sc(-c3ccc(F)cc3)cc12
Temperature: 60 °C
Yield: 54.6 %

Procedure:
To a solution of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (50 mg, 0.19 mmol) and BOP (110 mg, 0.25 mmol) in EtOH (1 ml) was added DBU (43 μl, 0.29 mmol). The resulting mixture was heated at 60° C. for 4 hours. After cooling down to room temperature, sodium ethoxide (26 mg, 0.38 mmol) was added. The mixture was again heated at 60° C. overnight. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) yielding the title compound as a white solid (30 mg, 54%). mp 142° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 30.2 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 70%, 0.53 g, 2.1 mmol) in chloroform (10 ml) was added dropwise to a solution of 2-{6-[(4-methylphenyl)sulfinyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one (0.35 g, 11.0 mmol) in chloroform (50 ml) with stirring. The reaction mixture was stirred at room temperature for 5 hrs and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethanol to give the titled compound (0.25 g, 64%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:24]1[S:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=1)[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCCl.C[Sn](C)(C)O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:24]1[S:25][C:26]([CH:29]=[O:30])=[CH:27][N:28]=1)[CH2:9][CH2:10][C@H:11]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)NC(=O)OC(C)(C)C
Agent: C[Sn](C)(C)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCN(C(=O)OC(C)(C)C)c1ncc(C=O)s1)C(=O)O
Temperature: 69 °C
Yield: 9.5 %

Procedure:
To a dry 2-5 mL microwave vial under N2 is added material from Example 116 (120 mg, 0.271 mmol) and anhydrous 1,2-dichloroethane (3 mL). The resulting solution is flushed with N2, treated with trimethylstannanol (60 mg, 0.332 mmol), securely capped and heated in a microwave heating unit at 60-78° C. for 6.5 h. The reaction is diluted with ethyl acetate (75 mL), and the organic layer is washed with 0.5N aqueous HCl (3×15 mL), brine (15 mL), dried over Na2SO4, filtered and evaporated to dryness to give 11 mg (95%) of the title compound as a pale yellow glass that contains 0.5 equivalents of the tin reagent. LC/MS (Condition A): ret. T=3.69 min, (M+Na) 452.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH2:47][CH3:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (189 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (300 mg, 0.97 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminothiazole (213 mg, 2.13 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (330 mg, 87%) as a pale yellow solid: mp 178-179° C.; EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1230.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:18](=[O:29])[N:19]([CH2:22][C:23]3[N:24]=[CH:25][NH:26][C:27]=3[CH3:28])[CH2:20][CH2:21][C:10]1=2.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH3:7])[S:3]([N:26]1[C:27]([CH3:28])=[C:23]([CH2:22][N:19]2[CH2:20][CH2:21][C:10]3[N:9]([CH3:8])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=3[C:18]2=[O:29])[N:24]=[CH:25]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C

Procedure:
A solution of dimethylsulphamoyl chloride (0.107 ml) in dry dichloromethane was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (0.294 g) and triethylamine (0.2 ml) in dry dichloromethane (30 ml) under nitrogen, and the mixture was heated at reflux for ca. 24 h. After cooling the solution was concentrated onto FCC silica and purified by FCC eluting with System A (150:8:1) to give an oil. This oil was triturated with ether to give a solid which was further purified by slow evaporation from a solution in ethyl acetate to give the title compound (122 mg), m.p. 194°-196°, t.l.c. (System A, 100:8:1) Rf 0.43.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C@H:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18].C(=O)([O-])O.[Na+]>C1COCC1>[CH3:8][S:9]([O:13][CH2:14][C@H:15]([NH:20][C:21]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Triethylamine (59 ml) and methanesulfonylchloride (25 ml) were added to a THF solution (200 ml) containing (R)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (46.2 g) in an ice bath, followed by stirring for 0.5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure. A white solid of (R)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (60 g) was thus obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=[C:7]2[CH2:6][N:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([N+:22]([O-])=O)[CH:16]=2)[C:4]1=[O:25])[CH3:2]>C(OCC)(=O)C.CO.[Pd]>[NH2:22][C:17]1[CH:16]=[C:15]([N:5]2[CH2:6][C:7]3[C:8](=[N:9][C:10]([S:13][CH3:14])=[N:11][CH:12]=3)[N:3]([CH2:1][CH3:2])[C:4]2=[O:25])[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(SC)nc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(SC)nc21
Yield: 30 %

Procedure:
To a solution of 1-ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (2.4 g, 6.5 mmol) in ethyl acetate and methanol (1:1, 40 mL) was added Pd/C (230 mg) and the mixture was hydrogenated (55 psi) in a Parr shaker for 2 days. The reaction mixture was filtered and the filter cake was washed with methanol. The combined filtrates were concentrated in vacuo. The residue was dissolved in THF and the solid was filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.65 g, 30% yield). 1H-NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1 H), 6.97 (m, 1 H), 6.70 (dd, J=8.0, 2.4 Hz, 1 H), 6.46 (m, 1 H), 5.21 (s, 2 H), 4.64 (s, 2 H), 3.94 (q, J=6.8 Hz, 2 H), 2.48 (s, 3 H), 1.15 (t, J=6.8 Hz, 3 H); MS (ESI) m/z: 334.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](S(C)=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:20]([O:30][CH3:31])(=[O:29])[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH3:31][O:30][C:20](=[O:29])[C@@H:21]([O:22][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)[C@@H](Oc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 10.9 %

Procedure:
A suspension of 2-methanesulfinylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (100 mg, 0.36 mmol) and (S)-(+)-methyl mandelate (86 mg, 0.52 mmol) in 3.6 mL of THF was treated dropwise with DBU (80 μL, 0.54 mmol) at room temperature. The reaction mixture clarified and turned yellow over the course of 5 min. The reaction was quenched after 24 hours by the addition of 5 mL 1 M HCl, followed by 25 mL of 1:1 (v:v) ethyl acetate:water. The mixture was extracted with 2×25 mL portions of ethyl acetate. The organic extracts were combined, dried using Na2SO4 and concentrated in vacuo. The crude material was dissolved in 30% (v/v)-ethyl acetate/hexanes and chromatographed through 15 g silica gel, followed by a second chromatography through 20 g silica gel. The product fractions were concentrated to yield 15 mg (11%) of the titled compound as a white solid. ESI-MS z/z 382 (MH+), 380 (M−H−).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](O)(=[O:15])[C:13]#[CH:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[C:13]#[CH:14]
Reactant: OCCOCc1ccccc1
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C#CC(=O)OCCOCc1ccccc1
Yield: 89.1 %

Procedure:
A mixture of 2 g of 2-benzyloxyethanol, 2.8 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 2.39 g of 2-benzyloxyethyl propiolate (compound 16).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20](O)([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCCC(O)(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC=C(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Temperature: 110 °C
Yield: 81.4 %

Procedure:
4-[7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]heptan-4-ol (594 mg) and p-toluenesulfonic acid monohydrate (74 mg) were combined in 13 mL toluene and the stirred mixture was heated to 110° C. for 11 h. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was washed with additional ethyl acetate. The combined ethyl acetate was washed with brine, dried with magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 461 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, which was recrystallized from hexane, mp 86.7–88.2° C.
Reaction SMILES: CCOCC.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH3:7].[N+:15]([O-])([OH:17])=[O:16]>O>[CH2:6]([C:8]1[C:9]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CCOCC
Product: CCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 130 ml of ether, 130 ml of water and 10.0 g of 2-ethylphenol was added dropwise 6.7 ml of 61% nitric acid, and the reaction was continued with stirring at room temperature for 4 hours. The reaction mixture was extracted with 300 ml of ethyl acetate and washed with a brine, and then dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform]to give 5.75 g of 6-ethyl-2-nitrophenol.
Reaction SMILES: C([O:8][C:9](=[O:17])[C@@:10]1([C:13]([F:16])([F:15])[F:14])[O:12][CH2:11]1)C1C=CC=CC=1.[H][H]>[Pt]=O.CO>[O:12]1[CH2:11][C@@:10]1([C:13]([F:16])([F:15])[F:14])[C:9]([OH:17])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@]1(C(F)(F)F)CO1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C(O)[C@]1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Into a 500 ml three-necked round-bottomed flask equipped with a stirrer, (S)-2,3-epoxy-2-trifluoromethylpropionic acid benzyl ester (20.9 g, 84.9 mmol, 99 ee %) was charged, and 180 ml of methanol was added for dissolution. Platinum oxide (1.63 g) was added, and then, the reaction system was substituted by hydrogen. After stirring at room temperature for 4 hours, platinum oxide was filtered off. The solvent was distilled off under reduced pressure, whereupon (S)-2,3-epoxy-2-trifluoromethylpropionic acid (11.9 g) was obtained (yield: 90%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:3][CH2:4][C:5]2[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=c1[nH]cccc1CO
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccc[nH]c1=O)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 14.94 %

Procedure:
In Example 2, 0.0725 g of 60% sodium hydride (NaH) was dispersed in mineral oil (1.60 mmol) and was suspended in 40 mL of THF in a 100 mL RBF under the presence of argon gas. Then, 0.2003 g (1.60 mmol) of 3-(hydroxymethyl)pyridine-2(1H)-one was added slowly and the solution stirred for 30 min with gentle heating before 0.250 mL (2.08 mmol) of 4-fluorobenzoyl chloride was added dropwise. The reaction was allowed to stir with gentle heating and for 48 hours. The reaction was quenched with the addition of 20 mL of water. The reaction was washed with ethyl acetate (4×20 mL) and the organic layers combined. The organic layer was washed with brine (3×20 mL) and dried over MgSO4. The solvent was evaporated in vacuo to produce a white solid. The product was purified by crystallization from toluene. The yield of the reaction was 0.0590 g (14.94% yield). MP: 170-173° C. IR (cm−1): 3415.21 (m, broad), υ (O—H), 3125.47 (m, broad), υ (N—H), 1716.90 (m), υ (C═O), 1614.44 (m), (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.13 (s, 2H), 6.23 (t, J=6.6 Hz, 1H), 7.37 (t, J=8.9 Hz, 2H), 7.41 (dd, J=4.5, 2.1 Hz, 1H), 7.59 (dd, J=4.7, 2.1 Hz, 1H), 8.06 (t, J=7.7 Hz, 2H), 11.78 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.ClCCl.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:38]=[C:37]([CH2:36][NH:35][CH3:34])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCNC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and N-methylpropargylamine (0.055 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 2% to 10% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4 N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, methanol-ether, toluene, and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.09 g of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:32]([C:28]3[C:27](=[O:35])[N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH:31]=[CH:30][CH:29]=3)=[O:33])=[CH:16][CH:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 50 °C
Reaction time: 12 h
Yield: 9.8 %

Procedure:
To a 2 dram vial was added N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.078 g, 0.3 mmol, prepared as described in Example XV1, step 1a), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10 g, 0.45 mmol, prepared as described in Example XVII, step 1e2), EDCI (0.086 g, 0.45 mmol), HOBt (0.061 g, 0.45 mmol), TEA (0.12 ml, 0.9 mmol), DMF (0.8 ml) and CH3CN (1.5 ml). The reaction was allowed to stir around 50° C. for 12 hrs. Upon cooling, the solvent was removed in vacuo and diluted with methanol (2 ml). The solution was purified by HPLC (20-100% methanol gradient), which yielded 0.014 g of the title compound as a TFA salt. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 11.88 (1H, s), 8.70 (1H, dd, J=7.12, 2.03 Hz), 7.71-7.91 (3H, m), 7.67 (1H, s), 7.50-7.63 (1H, m), 7.10-7.43 (5H, m), 6.64 (1H, s), 6.56 (1H, t, J=7.12 Hz). LC/MS, m/e 475 (M+1). HPLC Rt, 2.82 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f61) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[N:27][CH:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][N:27]=2)[CH3:32])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: CC(N)c1ccncn1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)c1ccncn1
Yield: 54 %

Procedure:
This compound (41 mg, 56% yield) as a yellow crystalline solid was prepared according the procedures described for Example 318, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (55 mg, 0.19 mmol), (1-(pyrimidin-4-yl)ethanamine dihydrochloride (73 mg, 0.37 mmol) (ChemBridge Corporation) and DIEA (0.26 mL, 1.48 mmol) in 2 mL of DMSO (heated in a microwave at 160° C. for 30 min)1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, br.), 9.15 (1H, s), 8.69 (1H, d, J=5.1 Hz), 7.87 (1H, d, J=7.2 Hz), 7.67 (2H, d, J=4.3 Hz), 7.57 (1H, d, J=8.0 Hz), 7.32 (1H, t, J=7.7 Hz), 6.99 (1H, br.), 6.87 (1H, s), 5.27 (1H, m), 3.48 (2H, m), 3.06 (2H, m), 2.69 (3H, s), 1.69 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 400.1 (M+H)+.