Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:42][CH:43]=[CH:44][C:30]=34)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccc(F)cc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(-c3ccc(F)cc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Yield: 92.1 %

Procedure:
(S)-tert-Butyl 2-(4-chlorophenyl)-3-(4-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (30 mg, 0.048 mmol) in TFA (3 mL) was stirred for 30 minutes and then concentrated to dryness. The resulting residue was dissolved in minimal DCM (0.2 mL) and added to 2N HCl in ether. The resulting solid was filtered and dried under nitrogen to yield (S)-2-(4-chlorophenyl)-1-(4-(5-(4-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (23 mg, 91% yield) dihydrochloride. MS ESI (+) m/z 520 detected.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:32])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[N:18][C:17]=2[CH:31]=1.CI>O1CCCC1>[F:28][C:22]([F:27])([C:23]([F:24])([F:25])[F:26])[C:21]([F:30])([F:29])[C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:12]([CH3:1])[C:11]([O:10][CH3:9])=[O:32])=[CH:31][C:17]=2[N:18]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc2oc(C(F)(F)C(F)(F)C(F)(F)F)nc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethyl benzene/heptane, 15.32 ml, 0.0306 mol) was added dropwise to a solution of methyl(2-heptafluoropropylbenzoxazol-5-yl)acetate (11.0 g, 0.0306 mol) in tetrahydrofuran (175 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (39.1 g, 0.275 mol) in tetrahydrofuran (25 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 3 hours. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give methyl 2-(2-heptafluoropropylbenzoxazol-5-yl)propionate (11.6 g) as a reddish oil, which was used without further purification in the next step.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](Br)=[CH:19][C:18]=1[C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.O1CCOCC1>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.CCCCCC.C(OCC)(=O)C>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:19][C:18]=1[C:32]1[O:36][N:35]=[C:34]([CH3:37])[C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)noc2-c2cc(-c3ccccc3)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 80 °C

Procedure:
Potassium phosphate (0.1 g, 0.5 mmol) was added to a solution of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (0.14 g, 0.25 mmol) and phenyl boronic acid (0.095 g, 0.75 mmol) in 1 dioxan (4 ml) under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium(0) (cat.) was added and the suspension heated, 80° C. for ˜18 hrs. The suspension was allowed to cool and ethyl acetate (25 ml) added. The mixture was washed with water (3×25 ml) and saturated aqueous sodium chloride solution (25 ml). The solution was dried over anhydrous magnesium sulphate and concentrated to give a pale brown gum. Trituration with hexane gave 5-(4,6-bis-benzyloxy-biphenyl-3-yl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole as an off-white solid, dried in vacuo.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1)(=O)=O>C(#N)C.C(O)C#C.C(N(CC)CC)C.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>[OH:9][CH2:8][C:7]#[C:12][C:7]1[C:12](=[O:13])[CH:11]=[C:10]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[O:9][CH:8]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1cc(COC2CCCCO2)occ1C#CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of 16 g of 4-oxo-6-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-3-yl trifluoromethanesulfonate in 100 mL of acetonitrile, 5.1 mL of propargyl alcohol, 18 mL of triethylamine, 0.62 g of dichlorobis(triphenylphosphine)palladium(II) and 0.42 g of copper (I) iodide were added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 97:3 to obtain 6.2 g of 5-(3-hydroxy-1-propyn-1-yl)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as a brown oily substance.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].I[C:17]1[CH:30]=[CH:29][C:28]2[O:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:31])[C:19]=2[CH:18]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:23]3[CH:24]=[CH:25][C:26]4[O:27][C:28]5[C:19](=[CH:18][CH:17]=[CH:30][CH:29]=5)[C:20](=[O:31])[C:21]=4[CH:22]=3)[CH2:11]2)[CH2:15]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=c1c2ccccc2oc2ccc(I)cc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4oc5ccccc5c(=O)c4c3)CC2C1
Temperature: 85 °C
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 3-Boc-3,7-diazabicyclo[3.3.0]octane (235 mg, 1.11 mmol; see WO 0181347), 2-iodoxanthen-9-one (362 mg, 1.12 mmol; see Example 52A), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3; 22 mg, 0.024 mmol; Alfa), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 37 mg, 0.059 mmol; Strem) and sodium tert-butoxide (166 mg, 1.73 mmol; Acros) in toluene (5 mL) was flushed with nitrogen and warmed to 85° C. with vigorous stirring for 6 h. The reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth with an EtOAc rinse, concentrated under reduced pressure, and purified by flash chromatography (35 g silica gel, 5-50% gradient of EtOAc in hexanes) to afford the title compound as a yellow foam (275 mg, 0.677 mmol; 61% yield): 1H NMR (300 MHz, CDCl3) δ ppm 8.35 (dd, J=8, 2 Hz, 1H), 7.69 (ddd, J=9, 7, 2 Hz, 1H), 7.47 (d, J=8 Hz, 1H), 7.43 (d, J=9 Hz, 1H), 7.30-7.38 (m, 2H), 7.05 (dd, J=9, 3 Hz, 1H), 3.57-3.73 (m, 4H), 3.24-3.45 (m, 4H), 2.97-3.12 (m, 2H), 1.46 (s, 9H); MS (DCI/NH3): m/z 407 (M+1)+.
Reaction SMILES: C([Al]CC(C)C)C(C)C.C1COCC1.C([O:17][C:18]([C:20]1[S:24][C:23]2=[CH:25][N:26]=[CH:27][N:22]2[C:21]=1[C:28](OCC)=[O:29])=O)C>C(OCC)C.O>[OH:17][CH2:18][C:20]1[S:24][C:23]2=[CH:25][N:26]=[CH:27][N:22]2[C:21]=1[CH2:28][OH:29]
Reactant: CCOC(=O)c1sc2cncn2c1C(=O)OCC
Agent: CC(C)C[Al]CC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCc1sc2cncn2c1CO
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A 1.33 ml potion of a 1.5M diisobutylaluminum hydridetoluene solution was added dropwise to 5 ml of an anhydrous THF solution containing 268 mg of 2,3-bis(ethoxycarbonyl)imidazo[5,1-b]thiazole in an argon atmosphere at -78° C., and the mixture was then stirred at the same temperature for 1 hour. Then, the reaction solution was diluted with 5 ml of diethyl ether, and 1.5 ml of water was then added thereto. After stirred at room temperature for 2 hours, the solution was filtered through Celite. The filtrate was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 148 mg of the title compound as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]([NH2:16])=O>O>[CH3:12][N:11]([CH3:13])[C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:14][NH:16][C:4]2=[O:6]
Reactant: NC=O
Reactant: CN(C)c1ccc(N)c(C(=O)O)c1
Solvent: O
Product: CN(C)c1ccc2nc[nH]c(=O)c2c1
Temperature: 25 °C

Procedure:
A mixture of 14.6 g. of 2-amino-5-dimethylaminobenzoic acid and 75 ml. of formamide is refluxed for 40 minutes, cooled to room temperature, 100 ml. of water added, the crystals broken up and recovered by filtering. After washing several times with water, the solids are dried to obtain 6-dimethylamino-quinazolin-4(3H)one, m.p. 233°-236° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[O:3]1.[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=1>C(#N)C>[F:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([B:4]3[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]3)=[CH:10][CH:11]=2)[CH:25]=1
Reactant: Nc1cc(F)ccn1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Solvent: CC#N
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (1.688 mmol, 450 mg) in acetonitrile (24.8 mL) was added 2-amino-4-fluoropyridine (4.22 mmol, 473 mg). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to a small volume, 3% aq. citric acid solution (18 mL) was added and the mixture was extracted with dichloromethane (2×15 mL). The combined organic layer was washed with 3% aq. citric acid solution, dried over magnesium sulfate, filtered and evaporated to afford 542.2 mg of N-(4-fluoropyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (94%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]([CH3:14])=[CH2:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1>[OH-].[Pd+2].[OH-].CO>[F:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:13])[CH3:14])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1
Reactant: C=C(C)c1nc2c(F)ccc(O)c2c(C)c1Cc1ccc(-n2cccn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(F)ccc(O)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.9 %

Procedure:
A mixture of 8-fluoro-2-isopropenyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.13 g), palladium hydroxide (0.047 g) and methanol (3.4 mL) was stirred at room temperature for 20 hours under an atmosphere of hydrogen. The mixture was filtered through Celite and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 1:1 by volume) gave title compound as a white foam (0.077 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22]C)=[C:15]([O:20]C)[CH:16]=3)[CH:11]2[CH3:24])=[CH:6][CH:5]=1.[BrH:27]>>[BrH:27].[BrH:27].[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([OH:22])=[C:15]([OH:20])[CH:16]=3)[CH:11]2[CH3:24])=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OC)C(C)N(CCc1ccc(N)cc1)CC2
Agent: Br
Agent: Cl
Product: CC1c2cc(O)c(O)cc2CCN1CCc1ccc(N)cc1
Reaction time: 1 h

Procedure:
N-(4-Aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride (10.0 g, 0.025 m) was dissolved in 49% HBr (25 ml) maintained under nitrogen and heated to 120° for 18 hr. after which time a white solid had precipitated. The mixture was cooled and the solid slurried with isopropanol (50 ml), stirred for 1 hr., and the solid collected by filtration. The solid was washed three times with isopropanol and vacuum dried at 100° for 48 hr. to give 8.5 g N-(4-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dihydroxy-1-methylisoquinoline dihydrobromide as an off-white solid, m.p. 275°-278°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:10][CH2:9][CH:8]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][CH2:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)=[N:13][N:12]=2)[CH2:7][CH2:6]1>ClCCl>[N:5]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:10][CH2:9][CH:8]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)Cl
Reactant: c1ccc(N2CCC(c3nnc4n3-c3ccccc3CNC4)CC2)nc1
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Acetyl chloride (22 mg, 0.29 mmol) was added to an ice cooled solution of the amine of example 1 (100 mg, 0.29 mmol) in dichloromethane (50 ml) and stirred at room temperature for 2 hours. The dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant to give the title compound as a brown foam (102 mg).
Reaction SMILES: Cl.[NH:2]([C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[C:5]=1[N:12]=O)[NH2:3].C(O[CH:17](OCC)[CH2:18][Cl:19])C>CN(C=O)C>[Cl:19][CH2:18][C:17]1[N:3]=[N:2][C:4]2[C:5](=[C:6]([NH2:11])[N:7]=[C:8]([NH2:10])[N:9]=2)[N:12]=1
Reactant: CCOC(CCl)OCC
Reactant: NNc1nc(N)nc(N)c1N=O
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(CCl)nnc2n1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Concentrated HCl (14 mL) was added to stirred ice cooled DMF (350 mL) followed by 7.14 g of 6-Hydrazino-5-nitroso-pyrimidine-2,4-diamine. After 5 min., chloroacetaldehyde diethylacetal (15.4 mL) was added over a ca. 2 min. period. The cooling bath was removed and the mixture allowed to come to room temperature. After 1 h, the mixture was warmed to 85° C. for 1.5 h and then allowed to cool to room temp over a 2.5 h period. The mixture was filtered to remove a small amount of brown insoluble material, the filtrate made alkaline with concentrated NH4OH solution and then diluted with an equal volume of water. The mixture was set aside for 1 h and then filtered to collect the orange/brown solid which was further dried in vacuo over P2O5 to give 3.50 g of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Reactant: N#CC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CCC(C#N)CC1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 25.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), piperidine-4-carbonitrile (3.58 mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.3 mg, 25.4%). 1H NMR (400 MHz, CD3OD) δ 0.84-0.93 (m, 3 H) 0.96-1.08 (m, 3 H) 1.42-1.60 (m, 1 H) 1.72-1.82 (m, 2 H) 1.82-2.00 (m, 1 H) 2.49-2.66 (m, 1 H) 2.92-3.07 (m, 1 H) 3.49-3.73 (m, 2 H) 3.78-4.00 (m, 1 H) 4.00-4.11 (m, 1 H) 4.90 (d, J=7.58 Hz, 1 H) 4.92-5.01 (m, 1 H) 5.53 (dd, J=10.86, 3.54 Hz, 1 H) 7.82-7.92 (m, 1 H) 8.15-8.30 (m, 1 H). [M+H] calc'd for C20H22ClN5O2, 400; found, 400.4.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[O:18]1[CH:19]=[CH:20][C:16]([CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)=[CH:17]1
Reactant: [N-]=[N+]=NCc1ccoc1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 53.9 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g, 0.384 mmol) was reacted with 3-azidomethyl-furan (0.057 g, 0.461 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.061 g, 54%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.61 (s, 1H), δ 7.46 (s, 1H), δ 6.42 (s, 1H), δ 6.38 (s, 1H), δ 5.41 (s, 2H), δ 2.95 (t, 2H), δ 2.83 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 146.3, 144.2, 141.6, 141.5, 126.5, 122.3, 120.2, 109.9, 109.1, 44.8, 24.2, 23.9 ppm; HRMS (ESI) calcd for C12H14N6O (M+) 259.1301. found 259.1306.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[NH:16][CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](=O)([O:33]C1C=CC=CC=1)[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 39, 8.49 g, 24.1 mmol) and diphenyl carbonate (5.42 g, 25.3 mmol) in THF (130 ml) at −78° C. was added slowly LHMDS (1 M in THF, 25.3 ml, 25.3 mmol). The reaction mixture was stirred at −78° C. for 30 min, then allowed to warm to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The combined organic phases were then dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (330 g silica gel cartridge, heptanes/EtOAc 100:0 to 50:50) to give the title compound as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.37-7.45 (m, 2H), 7.19-7.27 (m, 3H), 5.17 (s, 1H), 4.84 (s, 2H), 3.80-3.86 (m, 2H), 3.27 (s, 6H), 2.84 (t, 2H), 1.91-2.02 (m, 2H), 0.91 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])[CH3:5].[OH-].[Na+]>C1COCC1.CO.O>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])[CH3:5]
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of methyl 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoate (77.4 mmol) in a mixture of THF (232 mL) and methanol (232 mL) was treated with a solution of 2M sodium hydroxide (232 mmol), and the reaction mixture stirred for 4 hours at ambient temperature. The resulting solution was diluted with water (250 mL) and most of the organic solvent removed in vacuo. The resulting suspension was washed with diethyl ether (3×200 mL) and the organic washings discarded. The resulting aqueous solution was acidified to pH4 with 2M hydrochloric acid solution and extracted with ethyl acetate (2×200 mL). The extracts were combined, washed with brine, dried (MgSO4), and evaporated to give the desired compound (99% yield).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43]([C@H:45]1[CH2:49][CH2:48][C@@H:47]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:46]1)=[O:44])=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:44][C:43]([C@H:45]2[CH2:49][CH2:48][C@@H:47]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:54])[CH3:55])[CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a 0° C. solution of PPh3 (2.2 g 8.4 mmol) in dry DCM (20 mL) was added I2 (2.1 g, 8.4 mmol). After I2 was dissolved, TEA (2.4 mL, 16.8 mmol) was added quickly at rt. The reaction mixture was stirred for 15 min. tert-Butyl (1R,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopentylcarbamate (2.1 g, 4.2 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column (gradient elution 0˜50% EtOAc/petroleum ether) to afford the crude tert-butyl (1R,3S)-3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopentylcarbamate (˜1.7 g) as a white solid. ESI-MS (EI+, m/z): 484.1.