Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]#[N:8])=[O:5].[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>C(O)(=O)C.O.N1CCCCC1>[C:7]([C:6](=[CH:9][CH:10]([CH3:12])[CH3:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)C=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: CCOC(=O)C(C#N)=CC(C)C
Reaction time: 24 h
Yield: 43.9 %

Procedure:
A solution of piperidine (0.3 mL, 3.04 mmol) in acetic acid (3 mL) was added to a solution of ethyl cyano acetate (10 g, 88.50 mmol) and isobutyraldehyde (9.35 g, 0.13 mol) in acetic acid at room temperature. The reaction mixture was allowed to stand for 24 h at room temperature, then diluted with water (50 mL) and extracted with ether (3×50 mL). The combined ether layers were washed with saturated bicarbonate solution, water, and brine and the organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. Purification by vacuum distillation (95° C. at 0.1 mm Hg) afforded ethyl 2-cyano-4-methyl-pent-2-enoate (6.5 g, 30%) as a liquid.
Reaction SMILES: C([N:3](CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[Cl:13][C:14]1[CH:39]=[CH:38][C:17]2[N:18]3[C:22]([CH2:23][NH:24][CH2:25][C:16]=2[CH:15]=1)=[N:21][N:20]=[C:19]3[CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1>ClCCl>[NH3:3].[Cl:8][CH2:9][C:10]([N:24]1[CH2:23][C:22]2[N:18]([C:19]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[N:20][N:21]=2)[C:17]2[CH:38]=[CH:39][C:14]([Cl:13])=[CH:15][C:16]=2[CH2:25]1)=[O:11]
Reactant: CCN(CC)CC
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: N
Product: O=C(CCl)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (1.37 ml, 9.81 mmol) and chloroacetyl chloride (0.35 ml, 4.35 mmol) were added to a solution of the amine from example 4 (1.5 g, 3.95 mmol) in dichloromethane (50 ml), and the reaction stirred at room temperature for 2 hours. TLC analysis showed starting material remained, so additional chloroacetyl chloride (0.35 ml, 4.35 mmol) was added and the reaction was stirred for an additional 1.5 hours. The mixture was partitioned between dichloromethane and 2N sodium hydroxide solution and the layers separated. The aqueous phase was extracted with further dichloromethane and the combined organic solutions were washed with brine (50 ml), dried over magnesium sulphate, and evaporated under reduced pressure. The residual foam was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) to afford the title compound as a foam, 1.12 g.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[CH2:32][CH2:33][NH2:34].C(O)CCC>O>[ClH:13].[CH2:17]([O:16][C:14]([N:6]([CH2:5][CH:4]1[C:35]2[C:31](=[CH:30][C:29]([OH:28])=[C:37]([OH:38])[CH:36]=2)[CH2:32][CH2:33][NH:34]1)[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1ccc(Cl)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=C(OCc1ccccc1)N(CC1NCCc2cc(O)c(O)cc21)c1ccc(Cl)cc1
Yield: 111.3 %

Procedure:
N-benzyloxycarbonyl-p-chloroanilinoacetaldehyde diethyl acetal (10 g) and 3,4-dihydroxyphenethylamine hydrochloride (4.2 g) were added to a mixture of n-butyl alcohol (100 ml) and water (14 ml) and then the mixture was refluxed for 4 hours. The above-mentioned acetal (1 g) was added to the mixture and the resultant mixture was refluxed for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ethyl acetate and collected by filtration. The crystals were recrystallized from a mixture of methanol and ether to give 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (7.0 g), mp 210° to 212° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([C:25]#[N:26])=[CH:28][CH:29]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
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: CCO
Solvent: O
Product: N#Cc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)cc1
Temperature: 110 °C
Yield: 28.3 %

Procedure:
A vial was charged with a slurry of 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.256 mmol), (4-cyanophenyl)boronic acid (75 mg, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (29.5 mg, 0.026 mmol) and tripotassium phosphate (217 mg, 1.022 mmol) in ethanol (4.0 mL) and water (4.00 mL) then purged with nitrogen and sealed with a standard teflon septa (crimped aluminum seal). The reaction was then heated in an aluminum block at 110° C. for 2 h. The resulting yellow slurry was diluted with ethanol, treated with silica powder (2 g) then evaporated under reduced pressure. The dried powder was placed in a column adaptor (Analogix Dasi adapter) attached to a standard stock silica column (Analogix SF25-40 g) and eluted with ethyl acetate for 10 min and then with 7% methanol in dichloromethane. The combined desired fractions were evaporated to a colorless oil that was crystallized from hexanes/ethyl acetate to afford the title compound as a white solid (30 mg, 28.1%). MS(ES)+ m/e 414.2 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)[CH3:3]>CCO.C(Cl)Cl.[Pd]>[CH:2]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc2c(c1)nc(N)c1ncccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)nc(N)c1ncccc12
Reaction time: 8 h

Procedure:
A mixture of 8-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Pd/C (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The Pd/C was filtered off through celite, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-60% EtOAc/Hexanes to give 8-isopropylbenzo[f][1,7]naphthyridin-5-amine as a yellow solid: 1H NMR (acetone-d6): δ 8.98 (dd, 1H), 8.88 (dd, 1H), 8.37 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H), 7.27 (dd, 1H), 6.66 (br s, 2H), 3.10-3.00 (m, 1H), 1.33 (d, 6H). LRMS [M+H]=238.1.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1)#N.[OH-:24].[K+].C[OH:27]>O>[C:1]([CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1)([OH:27])=[O:24]
Reactant: [OH-]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC#N)no1
Reactant: CO
Agent: [K+]
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC(=O)O)no1

Procedure:
To a solution of 1.4 g of 3-cyanomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole obtained in Example 38 in 50 ml of methanol was added a solution of 2.56 g of potassium hydroxide in 23 g of water. After stirring under reflux for 4 hours, the reaction mixture was cooled, diluted with water and extracted with chloroform. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using chloroformmethanol (20:1, v/v) to give 1.35 g of 3-carboxymethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as an oil. It was crystallized from diisopropyl ether to give colorless fine needles, m.p. 100.5°-101.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[N:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:9]2)=[N:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2ncc(Br)cc2n1
Solvent: CCOC(C)=O
Product: Brc1cnc2ccc(N3CCOCC3)nc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 7-bromo-2-chloro-1,5-naphthyridine (F-31) (200 mg, 0.82 mmol, 1.0 eq) and morpholine (10 mL) was stirred in a sealed-tube at 140° C. overnight. The reaction mixture was cooled to RT, diluted with ethyl acetate (150 mL) and then washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product 7-bromo-2-morpholino-1,5-naphthyridine (F-32) (180 mg, 74.7% yield). ESI-MS m/z: 294.01 [M+H]+.
Reaction SMILES: CC([N:5]([CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:16]2[C:22](=[O:23])[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:14]=[C:15]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:16]2[C:22](=[O:23])[NH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Cc1cccc(Nc2nc(NCCCN(C(=O)[O-])C(C)(C)C)nc3cc[nH]c(=O)c23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(NCCCN)nc3cc[nH]c(=O)c23)c1
Reaction time: 1 h
Yield: 133.6 %

Procedure:
1,1-dimethylethyl[3-({4-[(3-methylphenyl)amino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-2-yl}amino)propyl]carbamate (245 mg, 0.577 mmol) was dissolved into dichloromethane (3 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 1 h and concentrated. The residue was further dried under high vacuum to afford the product as a TFA salt (250 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH2:14][CH2:13][CH2:12][O:11][C:10]=12)=[O:5].[CH3:16][Mg]Br.CCOCC>O1CCCC1>[N:8]1[N:9]2[C:10]([O:11][CH2:12][CH2:13][CH2:14]2)=[C:6]([C:4](=[O:5])[CH3:16])[CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cnn2c1OCCC2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cnn2c1OCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-carboxylic acid methoxy-methyl-amide (9.02 g, 42.7 mmol) in tetrahydrofuran (300 mL) was cooled to 0° C. 3 M methylmagnesium bromide in ether (15.3 mL, 43 mmol) was added and the reaction was stirred at 0° C. for 30 minutes, then warmed to room temperature. Additional 3 M methylmagnesium bromide in ether (15.3 mL, 43 mmol) was added after 1 hour, and the mixture was stirred at room temperature overnight, then the volatiles were removed in vacuo. The residue was partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (150 mL). The aqueous layer was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with brine (3×50 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (0 to 4% MeOH in DCM) afforded the ketone (5.79 g, 82%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ7.69 (s, 1H), 4.44 (t, 2H, J=5.25 Hz), 4.09 (t, 2H, J=6.10 Hz), 2.23 (s, 3H), 2.22-2.17 (m, 2H).
Reaction SMILES: CN(C=[O:5])C.[H-].[Na+].O[CH2:9][CH2:10][C:11]1[N:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:13]=[CH:14][N:15]=1.[F:27][C:28]([F:45])([F:44])[C:29]1[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]2[O:38][CH:39]=[C:40]([CH2:42]Cl)[N:41]=2)=[CH:31][CH:30]=1>O>[F:27][C:28]([F:45])([F:44])[C:29]1[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]2[O:38][CH:39]=[C:40]([CH2:42][O:26][C:23]3[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][CH2:16][N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]([OH:5])[CH3:9])=[CH:25][CH:24]=3)[N:41]=2)=[CH:31][CH:30]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(O)c1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under argon atmosphere, DMF (4 ml) was added to a mixture of 65% sodium hydride (40.6 mg) and 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) at 0° C. The mixture was stirred at room temperature for 30 min. [2-[(E)-2-(4-Trifluoromethylphenyl)ethenyl]oxazol-4-yl]methyl chloride (316 mg) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 15 hr. Water was added to the mixture to give crystals. The crystals were collected by filtration, washed with water and isopropyl ether and recrystallized from acetone-hexane to give the titled compound (393 mg) as pale yellow needle crystals.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3]([NH2:17])=[N:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of 5-iodo-2′-deoxycytidine (2.2 g, 6.23 mmol) in DMF (130 ml) was added imidazole (467 mg, 6.85 mmol). The mixture was cooled at 0° C. and tert-butyldimethylsilyl chloride (TBDMSCl) (1.33 g, 6.85 mmol) added over 5 minutes. After 18 h at room temperature, the volatiles were evaporated under reduced pressure and the residue purified by flash chromatography on silica gel with EtOAc:MeOH (95:5 to to 90:10) to give the expected product (39) (2.10 g, 72%) together with unreacted starting material (490 mg). 1H NMR (d6 DMSO) δ 0.11 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.89 (s, 9H, 3CH3), 1.90 (ddd, J=13.2, 7.7 and 5.7 Hz, 1H, HH-2′), 2.18 (ddd, J=13.2, 5.7 and 2.3 Hz, 1H, HH-2′), 3.72 (dd, J=11.5, 3.6 Hz, 1H, HH-5′), 3.80 (dd, J=11.5, 2.8 Hz, 1H, HH-5′), 3.86-3.89 (m, 1H, H-4′), 4.14-4.18 (m, 1H, H-3′), 5.22 (1H, d, J=4.1 Hz, OH), 6.09 (1H, dd, J=7.8, 5.8 Hz, H-1′), 6.60 (br s, 1H, NHH), 7.81 (br 9, 1H, NHH), 7.94 (s, 1H, H-6); MS (ES): m/z (%) (M+H) 468 (90%).
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:31][C@H:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:33]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])[N:8]=2)[CH2:6][CH2:5]1)=[O:34]
Reactant: Oc1ccccc1-c1nc(N2CCNCC2)c2ccccc2n1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.9 %

Procedure:
To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.82 mmol) in CH2Cl2 (6 mL) was added triethylamine (227 μL, 1.63 mmol) followed by the addition of (R)-2-hydroxy-4-methylpentanoic acid (140 mg, 1.06 mmol) and HATU (403 mg, 1.06 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with H2O. The aqueous layer was extracted twice with CH2Cl2, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in 50:50 CH2Cl2:hexanes gave (R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one (265 mg, 77%). LC/MS: m/z 421.30 (M+H)+ at 2.57 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J=8.3, 1.7 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H) 7.88 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.39 (m, 1H), 3.95 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.43 (m, 2H), 0.92 (q, J=3.8 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.30) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 58%). MS (ISP) 582.2 [(M+H)+]; mp 193–194° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:22]([NH2:24])=O)=[C:5]([NH:8][C:9](=[O:21])[CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][N:15]=[CH:16]3)[S:6][CH:7]=1)#[N:2].C[N:26]([CH:28](OC)OC)C.[NH2:33]N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:22]2[NH:24][N:26]=[CH:28][N:33]=2)=[C:5]([NH:8][C:9](=[O:21])[CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][N:15]=[CH:16]3)[S:6][CH:7]=1)#[N:2]
Reactant: N#Cc1csc(NC(=O)Cc2cccc3cnccc23)c1C(N)=O
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: ClCCl
Product: N#Cc1csc(NC(=O)Cc2cccc3cnccc23)c1-c1ncn[nH]1
Temperature: 95 °C

Procedure:
The title compound was prepared from 4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxamide (15 mg) according to protocol C except that DCM was added to the DMF-DMA step and refluxed while the hydrazine step was heated at 90° C. (rather than 95° C.). The product was purified via prep. HPLC to give N-(4-cyano-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl)-2-(isoquinolin-5-yl)acetamide. Method[7], MS(ESI) 361.1 [M+H], rt=1.273 min; 1H-NMR (300 MHz, CD3OD) δ 9.62 (b s, 1H), 8.60-8.57 (m, 1H), 8.44-8.37 (m, 2H), 8.34 (s, 1H), 8.29-8.20 (m, 1H), 8.04-8.0 (m, 1H), 7.86 (s, 1H), 4.56 (s, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@H:22]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:24]([CH2:52][O:53][CH2:54][C:55]2C=CC=CC=2)[O:23]1)[CH:2]=[CH2:3].ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=[O:67]>C(OC(=O)C)(=O)C>[C:54]([O:53][CH2:52][C@@H:24]1[C@@H:25]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:27]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@H:22]([C:6]2[CH:7]=[C:8]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=3)[C:9]([Cl:11])=[CH:10][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])[O:23]1)(=[O:67])[CH3:55]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -45 °C
Yield: 100 %

Procedure:
To a stirred −55° C. solution of (2S,3S,4R,5R,6R)-2-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (19, 8.54 g, 10 mmol) from Step 3 in acetic anhydride (50 mL)/dichloromethane (50 mL) was dropwise added trimethylsilyl trifluoromethanesulfonate (4.7 mL, 26 mmol) at a rate such that the reaction temperature was maintained between −50 and −55° C. The solution was allowed to warm to −45° C. over 1.5 h prior to quenching with saturated sodium hydrogen carbonate solution. The reaction mixture was extracted with dichloromethane and the combined organic layers were washed with saturated sodium hydrogen carbonate solution prior to drying over magnesium sulfate. After filtration and concentration under reduced pressure, the crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (20, 7.8 g, 10 mmol, 100%) as a white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:14]3=[N:15][C:16]([CH3:29])=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:21][CH2:20]4)=[C:13]3[C:12]([CH3:30])=[CH:11]2)=[C:5]([CH3:31])[CH:4]=1.Cl.[CH2:33]([O:35][C:36](=[O:46])[C@H:37]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:38])[CH3:34].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O.C(N(CC)CC)C>[CH2:33]([O:35][C:36](=[O:46])[C@@H:37]([NH:38][C:26](=[O:27])[CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:18]2[CH:17]=[C:16]([CH3:29])[N:15]=[C:14]3[N:10]([C:6]4[C:5]([CH3:31])=[CH:4][C:3]([Br:2])=[CH:8][C:7]=4[CH3:9])[CH:11]=[C:12]([CH3:30])[C:13]=23)[CH2:20][CH2:21]1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:34]
Reactant: Cc1cc(N2CCC(CC(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of {1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetic acid hydrochloride (300 mg), L-phenylalanine ethyl ester hydrochloride (204 mg), 1-hydroxybenzotriazole (108 mg) and triethylamine (90 mg) in DMF (3 mL) in an ice cooling bath was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (170 mg), and the mixture was stirred at room temperature for 4 hours. Water was added into the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous NaHCO3 solution and brine, and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=1/1) to obtain (S)-2-(2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetylamino)-3-phenyl-propionic acid ethyl ester (222 mg) as a colorless oil.