Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:11]=1.C[Al](C)C.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:21]([C:34](OCC)=[O:35])=[CH:20]2>>[O:10]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:34]([C:21]3[N:22]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)[C:23]4[C:19]([CH:20]=3)=[CH:18][C:17]([F:16])=[CH:25][CH:24]=4)=[O:35])=[CH:11][C:6]=2[CH2:7][CH2:8][NH:9]1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc2c(c1)CCNO2
Agent: C[Al](C)C
Product: O=C(Nc1ccc2c(c1)CCNO2)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 29.2 %

Procedure:
The process is performed according to the method described in Example 6, starting with 0.090 g of 6-amino-2,3-dihydrobenzoxazine (WO 2003/049702), 0.5 ml of trimethylaluminum (2M in toluene) and 0.157 g of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate, obtained in step 1.1 of Example 1. 0.061 g of product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:25])[C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O)[CH3:11].Cl>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:8]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:25])[CH3:11]
Reactant: NNc1ccc(Cl)nn1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(Cl)nn2)n1

Procedure:
3-Chloro-6-hydrazinopyridazine (1.59 g) and the 4-(2-pyridyl)-2,4-dioxobutanoic acid ethyl ester (2.45 g) obtained from Referential Example 31 in ethanol (60 mL) was refluxed under heat for 6 hours. To the reaction mixture, concentrated hydrochloric acid (1 mL) was added, and the mixture was refluxed under heat for 1 hour, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated brine, and then dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel chromatography (ethyl acetate-hexane), to thereby give 1-(6-chloro-3-pyridazinyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid ethyl ester as a solid (1.50 g, 41%).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
Acetaldehyde (84.5 μL, 1.51 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (91.0 mg, 0.188 mmol) in anhydrous methanol (10 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.638 g, 3.01 mmol) was then added in one portion and the reaction was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (35 mL) and sat. aq. NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×35 mL), the combined organic layers were washed with water (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue dissolved in DCM (5 mL) and MeOH (2 mL). Cyclohexane (20 mL) was added and the solvent removed in vacuo to afford a tan solid which was purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine 40-60° C.; then 0-75% MeOH in EtOAc) to yield a white solid. The solid was suspended in DCM (5 mL) and cyclohexane (20 mL) and filtered to afford the title compound (31) (40.7 mg, 42%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.26-7.12 (m, 6H), 6.92 (s, 1H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.05-2.92 (m, 4H), 2.43 (tt, J=11.7, 3.7 Hz, 1H), 2.33 (q, J=7.2 Hz, 2H), 1.93 (td, J=11.5, 2.1 Hz, 2H), 1.73 (dd, J=11.8, 2.0 Hz, 2H), 1.62 (ddd, J=24.8, 12.4, 3.6 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); LCMS Method C: rt 4.90 min; m/z 512 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].C(N(CC)CC)C>C(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: Nc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbonyl chloride (1.3 g, 10 mmol) (from Example 30) in DCM (20 mL) was added 3-fluoroaniline (1.2 g, 10.7 mmol) and triethylamine (1.5 mL). The mixture was stirred at room temperature for overnight. The reaction was washed with NaOH, water, brine, dried and concentrated to give 750 mg (37%) of 1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].N12CCN(CC1)CC2>C(Cl)Cl>[C:13](=[O:14])([O:8][CH:6]1[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]1)[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CC1(C)CC(OC(=O)Oc2ccccc2)CC(C)(C)N1
Reaction time: 2 h

Procedure:
Into a 500 ml 3-neck flask was added 23.2 grams (0.14 mole) of 95% 2,2,6,6-tetramethyl-4-piperidinol and 400 ml of methylene chloride. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 11.2 grams (0.07 mole) of phenyl chloroformate. The phenyl chloroformate was slowly added to the 2,2,6,6-tetramethyl-4-piperidinol solution without any appreciable exotherm. Then 0.5 grams of 1,4-diazabicyclo(2.2.2)octane (DABCO) was added at room temperature. The temperature rose to 35° C. and a precipitate formed. Another 0.5 gram of DABCO was added but no further exotherm occurred. After stirring for 11/2 hours, the solids were filtered off and the methylene chloride solution was washed with water, 10% NaOH and water again, dried over anhydrous MgSO4, filtered and the solvent stripped off on a rotating evaporator under reduced pressure. The residue was a white solid weighing 17.4 grams (90% crude yield) which had a melting point of 62°-65° C. Liquid chromatography indicated the product was essentially one component. The infrared spectrum contained a strong carbonyl peak at 1760 cm-1 and a moderate carbonyl peak at 1710 cm -1.
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[C:28]([NH:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)nn3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (120 mg, 0.333 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (24.0 μL, 0.338 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (89.1 mg, 66%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:21]([F:24])([F:23])[F:22])=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[N:18]1[CH:19]=[CH:20][C:15]([C:13]2[N:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[O:11][C:12]=2[C:21]([F:24])([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
to a nitrogen purged flask charged with palladium on carbon (0.032 g, 0.30 mmol) and 4-(2-(4-nitrophenyl)-5-(trifluoromethyl)oxazol-4-yl)pyridine (1.015 g, 3.0 mmol) in 40 mL ethyl acetate was introduced hydrogen (0.0061 g, 3.0 mmol) by balloon. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen for 18 h then purged with nitrogen and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford a yellow solid. The desired product was isolated by chromatography on silica, eluting with 100% ethyl acetate, affording product as a colorless solid (0.52 g, 56%). ESI+ m/z=306.1 [MH]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: Clc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(Cl)cc3)c3nc[nH]c3n2)CC1

Procedure:
2850 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 2260 mg of the product obtained in stage 1 above are added. 80 mg of the expected product are thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:52]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 41.3 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0319 g, 0.0691 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2-trifluoromethylbenzenesulfonyl chloride (0.0301 mL, 0.195 mmol) to obtain 4-(2-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0191 g, yield 41%).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].[Cl-].[NH4+]>O.O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1)[OH:18]
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(C(O)(c2ccccc2)c2ccccc2F)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a stirred and refluxing Grignard complex previously prepared starting from 80.2 parts of 4-chloro-1-methylpiperidine, 14.6 parts of magnesium and 270 parts of tetrahydrofuran, was added dropwise a solution of 101 parts of (2-fluorophenyl)phenylmethanone in 450 parts of tetrahydrofuran. Upon completion, stirring was continued for 18 hours at reflux temperature. The reaction mixture was cooled in an ice-bath and decomposed with a solution of 32 parts of ammonium chloride in 160 parts of water. After stirring for 30 minutes, the product was filtered off and washed with tetrahydrofuran. The filtrate was evaporated, the residue was taken up in methylbenzene and the latter was evaporated again in a boiling water-bath. The residue was dissolved in 700 parts of 2,2'-oxybispropane. The turbid solution was filtered and gaseous hydrogen chloride was bubbled through the filtrate. The solid product was filtered off and suspended in 1000 parts of water. The suspension was treated with ammonium hydroxide and extracted twice with 280 parts of 1,1'-oxybisethane. The combined extracts were dried, filtered and evaporated. The oily residue was crystallized from 240 parts of acetonitrile. After cooling to 0° C., the product was filtered off and dried, yielding 66 parts (44%) of α-(2-fluorophenyl)-1-methyl-α-phenyl-4-piperidinemethanol (intermediate 33).
Reaction SMILES: [CH2:1]([CH:4]([N:8]1[C:12]2[N:13]=[C:14]([CH3:27])[N:15]=[C:16]([NH:17][C:18]3[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[C:11]=2[N:10]=[N:9]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O.O>[CH2:30]([N:17]([C:18]1[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=1[CH3:24])[C:16]1[C:11]2[N:10]=[N:9][N:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[C:12]=2[N:13]=[C:14]([CH3:27])[N:15]=1)[CH3:31]
Reactant: CCCC(CCC)n1nnc2c(Nc3c(C)cc(C)nc3C)nc(C)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)n1nnc2c(N(CC)c3c(C)cc(C)nc3C)nc(C)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from Example 47, Part B (400 mg, 1.09 mmol) was treated with sodium hydride (40 mg, 1.31 mmol, 80%) and ethyl iodide (0.130 ml, 1.63 mmol) in dry dimethylformamide (10 ml) and stirred at room temperature for 15 hours. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 373 mg (87%) as a clear viscous oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C(COC)OC.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1B(O)O>C(OCC)(=O)C.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>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:31]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=3[CH3:29])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc3c2c(=O)c(C)nn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To 0.115 g (0.40 mmol) of 1-benzyl-5-chloro-3-methylcinnolin-4(1H)-one, 0.12 g (0.81 mmol) of cesium fluoride and 0.093 g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) was added 4 mL of dimethoxyethane. The dark brown mixture was stirred at room temperature for 15 min. then 0.079 g (0.53 mmol) of 2,4-dimethylphenylboronic acid was added. This mixture was then heated to reflux for 5 h, cooled to room temperature, diluted with ethyl acetate and filtered through a plug of silica gel. The resulting filtrate was concentrated and the residue was purified by flash chromatography eluting with a 17% ethyl acetate/hexanes mixture to give 0.102 g (71%) of the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.[C:19]([O-:22])([O-])=[O:20].[Cs+].[Cs+].CO>COCCOC.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>[NH2:16][C:13]1[N:12]=[CH:11][C:10]([C:9]#[C:8][C:7]2[C:2]([C:14]3[CH:15]=[CH:10][C:11]([C:19]([OH:22])=[O:20])=[N:12][CH:13]=3)=[N:3][CH:4]=[N:5][C:6]=2[CH2:17][CH3:18])=[CH:15][CH:14]=1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Product: CCc1ncnc(-c2ccc(C(=O)O)nc2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C

Procedure:
The title compound is synthesized in analogy to general procedure GP4 starting from 1.2 g (4.63 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine using 1.0 g (5.6 mmol) 4-methoxycarbonyl-3-pyridyl boronic acid, 163 mg (0.23 mmol) bis-(triphenylphoshine)palladium(II) chloride, 7.0 mL (13.9 mmol) of an aqueous 2 M Cs2CO3 and 2 mL MeOH in 10 mL DME. The reaction mixture is stirred over night at 80° C. The reaction mixture is poured on water and washed with DCM. Aqueous 1 M HCl is added to the aqueous phase until pH 5 is reached. The precipitated product is filtered off and washed with water and methanol. After drying 290 mg (13%) of the desired product are obtained a solid material which is used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1>CCOC(C)=O>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: Clc1cnccn1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2cnccn2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
Into a 250 mL roundbottom flask, was placed methyl 4-aminobenzoate (vii) (10 g, 66.23 mmol) followed by the addition of 2-chloropyrazine (75.9 g, 665.79 mmol). The resulting solution was stirred at 150° C. for 4 hours. The reaction progress was monitored by TLC (EtOAc/PE=1:2). After completion, the reaction was cooled to room temperature and the undissolved material was filtered off. The filtration was dissolved in 400 mL of water and the pH was adjustmented to 9 by the addition of Na2CO3. The resulting solution was extracted four times with 800 mL of EtOAc and the organic layers were combined and dried over Na2SO4. Removal of the solvent and volatile components from the organic layer under reduced pressure provided the crude product methyl 4-(pyrazin-2-ylamino)benzoate (viii) (13.6 g, 90% yield) as a yellow solid which was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[S:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH2:27])[C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2.Cl.C(N(CC)CC)C>>[S:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH:27][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCCc1csc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCc4csc5ccccc45)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared as in Example 1 using 6-chloropurine riboside (1.15 g, 4 mmol), 2-(3-benzo[b]thienyl)ethylamine.HCl (CAS Number 148585-66-1) (1.0 g, 4.6 mmol), and triethylamine (1.1 g, 11 mmol); yield 1.5 g (88%), mp 173°-174° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:16]2[C@@H:15]3[C@H:10]([CH2:11][NH:12][CH2:13][CH2:14]3)[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>>[ClH:1].[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][C@@H:15]3[C:16]4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=[CH:7][C:8]=4[CH2:9][C@H:10]3[CH2:11]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(NCCBr)c1ccc(F)cc1
Reactant: COc1cccc2c1[C@H]1CCNC[C@@H]1C2
Agent: Cl
Product: COc1cccc2c1[C@H]1CCN(CCNC(=O)c3ccc(F)cc3)C[C@@H]1C2
Yield: 32.5 %

Procedure:
The product from Example 48 (0.310 g) was treated with 0.34 g 2-bromo-1-(4-fluorobenzamido)ethane as described as described in Example 7 to yield 0.170 g of the desired product as a white solid, mp: 242-4° C. NMR (d6DMSO) δ 1.95 (m, 2H), 2.29 (m, 2H), 2.45-2.75 (m, 2H), 2.82 (m, 2H), 3.05-3.45 (m, 4H), 3.60-3.90 (m, 2H), 3.77 (s, 3H), 6.80 (d, 1H), 6.87 (d, 1H), 7.13 (t, 1H), 7.31 (m, 2H), 8.00 (m, 2H), 8.98 (m, 1H).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:72]2[N:73]=[C:74]([NH:77]C(OC(C)(C)C)=O)[S:75][CH:76]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43]([N:52](C(OC(C)(C)C)=O)[CH2:53][CH:54]3[CH2:57][N:56](C(OC(C)(C)C)=O)[CH2:55]3)=[N:44]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:77][C:74]1[S:75][CH:76]=[C:72](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43]([NH:52][CH2:53][CH:54]3[CH2:55][NH:56][CH2:57]3)=[NH:44])[CH:38]=[N:37]2)=[O:24])[N:73]=1
Reactant: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1)NCC1CNC1
Yield: 12 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((2,3-bis(tert-butoxycarbonyl)-3-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)guanidino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (300 mg, 0.248 mmol), DCM (3 mL) and TFA (1.90 mL, 24.85 mmol). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 24 mL/min) affording the title compound (19 mg, 12%). LCMS: Rt=0.32 min, m/z=641.3 (M+1), Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 10.26 (br s, 1H), 8.79 (br s, 3H), 7.78-7.54 (m, 3H), 7.14 (s, 2H), 6.84 (s, 1H), 5.06 (br s, 1H), 4.88 (dd, J=14.1, 3.94 Hz, 1H), 4.70-4.59 (m, 1H), 4.54-4.46 (m, 1H), 4.35 (d, J=3.8 Hz, 2H), 4.00-3.89 (m, 2H), 3.76-3.65 (m, 2H), 3.08-2.94 (m, 1H), 1.30-1.09 (m, 4H).