Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li+].CC([N-]C(C)C)C.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23].[NH4+].[Cl-]>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[C:3]2[S:10][C:9]([Sn:19]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ncnc2ccsc12
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ncnc(Cl)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flame dried flask was placed a suspension of compound 6.2 (5.92 mmol) in THF (50 mL). The reaction was cooled to −78° C. and a solution of LDA (3.25 mL of a 2.0 M solution in heptane/THF/ethyl benzene) was slowly added. After stirring for 30 minutes, a −78° C., a solution of (n-Bu)3SnCl (1.9 mL) in THF (50 mL) was added via cannula over a 20 minute period at −78° C. and stirred for 2 hours. The reaction was warmed to room temperature, hydrolyzed with saturated NH4Cl, extracted with EtOAc, dried and concentrated. The crude product was purified by flash column chromatography on silica gel (1:1 hexanes/dichloromethane then 10% EtOAc/dichloromethane) to provide 4-chloro-6-tributylstannanyl-thieno[3,2-d]pyrimidine (compound 52.1) in 92% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1.Cl.[CH:18](OCC)=[O:19]>>[CH3:3][S:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH:18]=[O:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1ccc(SC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (0.84 g, 20.8 mmol) was added at room temperature to a solution of ethyl 4-methylthiophenylacetate (1.1 g, 5.2 mmol) in ethyl formate (20 mL). The mixture was stirred at room temperature for 1 hour and then cold 0.5 N HCl (20 mL) was added slowly. The crude reaction was then extracted with ether, and the organic layer was washed with sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and concentrated to yield 1.2 g of ethyl 4-methylthio-α-formyl-phenylacetate as a colorless oil, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]5[S:37][CH:41]=[CH:40][CH:39]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[O:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CN(C)CCOc1cc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)ccc1Cl
Product: CN(C)CCOc1cc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)ccc1Cl
Yield: 70 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-chloro-3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine using 2-thienylacetyl chloride as described in Example 10, Step E to give a yellow solid in 70% yield. 1H NMR (300 MHz, DMSO-D6) δ ppm 2.2 (s, 6H) 2.6 (t, J=5.8 Hz, 2H) 3.9 (s, 2H) 4.0 (t, J=6.0 Hz, 2H) 6.6 (d, J=5.2 Hz, 1H) 7.0 (d, J=4.2 Hz, 2H) 7.2 (m, 1H) 7.3 (m, 1H) 7.4 (m, 2H) 7.5 (s, 1H) 7.6 (s, 1H) 7.8 (m, 2H) 7.9 (s, 1H) 8.3 (d, J=5.2 Hz, 1H) 8.5 (d, J=9.7 Hz, 1H) 8.9 (d, J=6.7 Hz, 2H) 9.7 (s, 1H) 10.4 (s, 1H). ES-LC/MS m/z 624 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[BrH:14]>O>[Br:14][C:3]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[I:1]
Reactant: Br
Reactant: Cc1ccc(N)c(I)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)c(I)c1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
2-Iodo-4-methylaniline (100 g, 450 mmol) was suspended in the mixture of water (200 mL) and HBr (48%, 300 mL). The mixture was refluxed for 15 min. Then the mixture was cooled to 0° C., and NaNO2 (31.05 g, 0.45 mol) in water (150 ml) was added dropwise at such a rate that the temperature did not exceed 5° C. The diazonium solution wad stirred for a further 30 min at 0-5° C. and then added slowly to a stirred mixture of CuBr (64.5 g, 0.45 mol) in HBr (48%, 250 mL) and water (250 ml) at room temperature. The mixture was poured into ice and extracted with CH2Cl2 (500 ml×3). The methylene chloride layer was washed with brine, dried over Na2SO4, and evaporated in vacuum to give the crude product (109 g, yield 81.8%). It can be further purified by column chromatography eluting with petroleum ether. MS: 297 [M+1]+.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:19][CH:18]=[CH:17][CH:16]=2.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:21]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[CH:1]1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cccnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3cccnc3c21
Yield: 21.3 %

Procedure:
Triethylorthoformate (2.8 mL, 16.6 mmol) was added to a solution of 1,1-dimethylethyl N-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (5.0 g, 15.1 mmol) in toluene (150 mL). The reaction was heated at reflux overnight with ethanol being collected in a Dean Stark trap. The reaction mixture was heated at reflux for an additional 6 hours and then p-toluenesulfonic acid (1.4 g, 7.5 mmol) was added and the reaction was refluxed overnight. A dark orange/brown oil had formed. The toluene supernatant was decanted off and concentrated under vacuum to provide 1.1 g of 1,1-dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The oil was identified as 4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine. This material was reacted with 1,1-dimethylethyl-dicarbonate to provide an additional 1 g of 1,1-dimethylethyl N-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The two lots were combined and carried on to the next step.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](B(O)O)[CH:27]=2)[CH:22]=[N:21]1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(Cl)Cl.O.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>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[CH:27]=2)[CH:22]=[N:21]1
Reactant: CC(C)n1cc(Nc2nc(Br)cn3ccnc23)cn1
Reactant: OB(O)c1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)n1cc(Nc2nc(-c3ccc4cn[nH]c4c3)cn3ccnc23)cn1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
A mixture of impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (195 mg), from above, and 1H-indazol-6-ylboronic acid (159 mg, 0.650 mmol) in 1 M aqueous sodium carbonate (1.3 mL) and 1,4-dioxane (3.5 mL) was sparged with nitrogen while stirring for 5 min. Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.060 mmol) was then added and the resulting mixture heated under microwave irradiation at 135° C. for 30 min. After this time, the reaction was diluted with methylene chloride (30 mL) and water (20 mL), and filtered through diatomaceous earth. The filtrate layers were separated and the aqueous phase was extracted with a mixture of 9:1 methylene chloride/methanol (100 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by chromatography (silica, gradient, methylene chloride to 8:2 methylene chloride/methanol), then trituration with acetonitrile to afford 6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (5) (85 mg, 35%) as a yellow solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.95 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.75 (dd, J=8.7, 1.2 Hz, 1H), 7.62 (s, 1H), 4.52 (m, 1H), 1.47 (d, J=6.6 Hz, 6H); ESI MS m/z 359.4 [M+H]+; HPLC, 5.37 min, >99% (AUC).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[CH:25]=[C:24]([CH:26]=O)[N:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:33]([NH2:39])[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[CH2:29]([CH:28]([N:23]1[C:21]2[N:22]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)[N:18]=[CH:19][C:20]=2[CH:25]=[C:24]1[CH2:26][NH:39][CH2:33][C:34]1[O:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reactant: NCc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(CC)n1c(CNCc2ccco2)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (30 mg, 0.07 mmol) in THF (1 mL) is added furfurylamine (0.03 mL, 0.35 mmol), NaBH(OAc)3 (45 mg, 0.21 mmol), and acetic acid (1 mL). The reaction mixture is stirred for 16 h and concentrated in vacuo. The residue is purified by preparative HPLC to give 20 mg of 1-{4-[4-(7-(1-ethyl-propyl)-6-{[(furan-2-ylmethyl)-amino]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazin-1-yl}-ethanone as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH2:6][NH2:7])=[C:4]([CH3:11])[CH:3]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH2:6][N:7]=[C:13]=[O:15])=[C:8]([CH3:10])[CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Br)cc(C)c1CN
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: Cc1cc(Br)cc(C)c1CN=C=O

Procedure:
The title compound was prepared from 4-bromo-2,6-dimethyl-benzylamine and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 1. Mass spectrum (EI): m/z=239/241 (Br) [M]+.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]=[C:18]=[O:19]>C(N(CC)CC)C>[CH3:16][NH:17][C:18]([N:7]1[C:8]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:19]
Reactant: CN(C)S(=O)(=O)c1nnc(C(C)(C)C)[nH]1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(C(C)(C)C)nc1S(=O)(=O)N(C)C

Procedure:
A solution of 8.0 g (0.034 mols) of 3-tert.butyl-4H-1,2,4-triazol-5-yl-N,N-dimethylsulfonamide and 3.4 g (0.06 mol) of methyl isocyanate in 20 ml of triethylamine is stirred overnight at room temperature. The solvent is evaporated under vacuum and the residue is slurried in water. The resultant solid is collected by filtration and recrystallized from ethanol to give 1-N-methylcarbamyl-3-tert.butyl-1,2,4-triazol-5-yl-N,N-dimethylsulfonamide, m.p. 193°-194.5°.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1.Cl.N[C@H:24]1[CH2:28]CN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)[CH2:25]1>>[CH2:28]([NH:2][CH:3]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[C:12]3[C:13]([Br:21])=[CH:14][N:15]=[CH:16][C:17]=3[CH:18]=[CH:19][CH:20]=2)(=[O:10])=[O:9])[CH2:4]1)[CH:24]=[CH2:25]
Reactant: NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Product: C=CCNC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1

Procedure:
3-Amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride can be used in the method of Example 5-1 instead of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine hydrochloride to obtain the title compound.
Reaction SMILES: [N:1]([C@H:4]([C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[C:2]=[S:3].[C:26]([NH:29][NH2:30])(=O)[CH3:27]>CCO>[CH3:27][C:26]1[S:3][C:2]([NH:1][C@H:4]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:18][CH:19]=2)[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[N:30][N:29]=1
Reactant: O=[N+]([O-])c1ccc(C[C@H](N=C=S)c2csc(-c3ccccc3)n2)cc1
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1nnc(N[C@@H](Cc2ccc([N+](=O)[O-])cc2)c2csc(-c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A solution of (S)-4-(1-isothiocyanato-2-(4-nitrophenyl)-ethyl)-2-phenylthiazole, 4, (332 mg, 0.876 mmol) and acetic hydrazide (65 mg, 0.876 mmol) in EtOH (5 mL) is refluxed for 2 hours. The solvent is removed under reduced pressure, the residue is dissolved in POCl3 (3 mL) and the resulting solution is stirred at room temperature for 18 hours after which the solution is heated to 50° C. for 2 hours. The solvent is removed in vacuo and the residue is dissolved in EtOAc (40 mL) and the resulting solution is treated with 1N NaOH until the pH remains approximately 8. The solution is extracted with EtOAc. The combined aqueous layers are washed with EtOAc, the organic layers combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford 0.345 g (93%) of the desired product as a yellow solid. 1H NMR (CDCl3) 8.09 (d, J=8.4 Hz, 2H), 7.91 (m, 2H), 7.46 (m, 4H), 7.44 (s, 1H), 5.23 (m, 1H), 3.59 (m, 2H), 2.49 (s, 3H). ESI+MS 424 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:31]([O:38][C@H:39]1[C@H:44]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:43]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:42]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67][CH3:68])=[C:63]([CH2:69][C:70]3[CH:79]=[CH:78][C:73]4[O:74][CH2:75][CH2:76][O:77][C:72]=4[CH:71]=3)[CH:62]=2)[O:41][C@@H:40]1[CH2:80]O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:31]([O:38][C@H:39]1[C@H:44]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:43]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:42]([C:61]2[CH:66]=[CH:65][C:64]([CH2:67][CH3:68])=[C:63]([CH2:69][C:70]3[CH:79]=[CH:78][C:73]4[O:74][CH2:75][CH2:76][O:77][C:72]=4[CH:71]=3)[CH:62]=2)[O:41][C@@H:40]1[CH2:80][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:13]([CH3:15])[CH3:14])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1ccc([C@@H]2O[C@H](COC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (6.3 g, 29.1 mmol) in DMF (40 ml) was added N,N′-dicyclohexylcarbodiimide (6.0 g, 29.1 mmol). After stirring for 30 min at room temperature, reaction mixture was cooled to 0° C., added a solution of {(2R,3R,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-yl}-methanol (4.0 g, 5.8 mmol) in DMF (20 ml) followed by DMAP (360 mg, 2.9 mmol) and stirred at ambient temperature for overnight. Reaction was quenched by the addition of water (150 ml) and extracted with ethyl acetate (2×80 ml). Combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 4.5 g of (R)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (2R,3R,4R,5S,65)-3,4,5-tris-benzyloxy-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-tetrahydro-pyran-2-ylmethyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O.C(OCC)(=O)C>[CH2:19]([O:26][C:27]([N:11]1[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.05 g 3-(tert-butoxycarbonylamino)pyrrolidine, 1.85 g NaHCO3 and 3.17 g N-(Benzyloxycarbonyloxy)succinimide in 10 ml dioxane/water 1:1 was stirred for 12 h at RT. The reaction mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with saturated NaHCO3 and brine. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1.O>CN(C)C=O>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[N:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cccnc3c2=O)cc1C
Reaction time: 0.08 h
Yield: 12.2 %

Procedure:
To a solution of 0.060 g (0.216 mmol) of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one in 2.0 mL of N,N-dimethylformamide was added 10.4 mg (0.259 mmol, 60% dispersion in oil) of sodium hydride and the reaction was stirred for 5 min. 65 mg (0.259 mmol) of 2-bromo-6-bromomethyl-pyridine was added and the reaction was stirred at room temperature for 3 h. Water was added and the solid collected by filtration. The crude brown solid was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 11.8 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]([CH3:16])[C:9]=2[NH:17][C:18]=1[CH:19]([CH3:21])[CH3:20])=[O:5])[CH3:2]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:18]([CH:19]([CH3:21])[CH3:20])=[N:17][C:9]2[N:10]([CH3:16])[C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C(C)C)Nc2c(c(=O)[nH]c(=O)n2C)C1c1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.35 g (50 mmol) of 2,3-dichloro-4,5-dicyanobenzoquinone are added to a suspension of 19.4 g (50 mmol) of the compound from Example 10 in 1 1 of dichloromethane and the mixture is stirred at room temperature for 2 h. It is then washed three times with water, and the organic phase is treated with sodium sulphate and active carbon, filtered and concentrated to dryness. 17.5 g (91% of theory) of colorless solid remain.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20](OCCN(CC)CC)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[Cl:33]C1N=C(C=O)C=CC=1.C(CC(N[C@H](C1C=CC=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:33])[N:7]=1)/[C:10]([NH:12][C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: O=Cc1cccc(Cl)n1
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Agent: CCC[C@H](NC(=O)CC#N)c1ccccc1
Product: CCC[C@H](NC(=O)/C(C#N)=C/c1cccc(Cl)n1)c1ccccc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-chloropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and (S)-2-cyano-N-(1-phenylbutyl)acetamide was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 8:2 hexanes/ethyl acetate, to give 41 (105 mg, 95%) as a clear oil: MS (ES+) m/z340.1 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24]>C(O)C>[C:20]([C:21]1[CH:22]=[C:23]([NH2:24])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([CH3:27])([CH3:26])[CH3:19]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Yield: 70 %

Procedure:
N,N-Diisopropylethylamine (1.7 mL, 7.99 mmol) was added to a mixture of phenyl hydrazine hydrochloride (1.5 g, 10.39 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.0 g, 7.99 mmol) in ethanol (15 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then concentrated to low volume and partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with heptanes:ethyl acetate, 75:25, to afford the title compound as a pale orange oil that crystallised on standing (1.21 g, 70% yield).