Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]([C@@H:7]2[CH2:12][C@H:11]([N:13]([C:18]([C:20]3[C:21]([NH:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[N:22][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[N:24][CH:25]=3)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.Cl>[N:1]1([C:5]([C@H:7]2[CH2:8][NH:9][CH2:10][C@@H:11]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([C:20]3[C:21]([NH:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])=[N:22][C:23]([C:26]([CH3:28])([CH3:29])[CH3:27])=[N:24][CH:25]=3)=[O:19])[CH2:12]2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
tert-Butyl (3R,5S)-3-(azetidin-1-ylcarbonyl)-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (94 mg) was dissolved in 4 M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to reversed-phase preparative HPLC. Aqueous sodium hydrogen carbonate was added to the object fraction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (33 mg).
Reaction SMILES: C[O-].[Na+].Br[C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([I:13])[N:6]=1.[C:14]([O-])(O)=[O:15].[Na+].C(Cl)Cl>CN(C=O)C>[I:13][C:7]1[N:6]=[C:5]([O:15][CH3:14])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(I)nc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C

Procedure:
Add NaOMe (1.4 equiv., 1.25 g, 23.14 mmol) to 2-bromo-6-iodo-3-methoxypyridine, 3 (4.95 g, 15.76 mmol) dissolved in DMF (10 mL), and stir the reaction medium, heating at 100° C. under N2 for 1 h. After cooling, the reaction mixture is shared between saturated NaHCO3 and CH2Cl2, and the organic phase is dried (MgSO4) and concentrated. Purification on SiO2 (EtOAc at 10%/heptane) gives 4 (3.13 g, 74.9% as a white solid: 1H NMR (CDCl3) δ 7.25 (d, 1H, J=7.8 Hz), 6.76 (d, 1H, J=8.1 Hz), 4.03 (s, 3H), 3.87 (s, 3H); m/z obs.=266 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.CO>[NH2:7][C@@H:8]1[CH2:9][N:10]([C:15]([C:17]2[CH:39]=[C:38]([O:40][CH3:41])[C:20]3[N:21]([CH3:37])[C:22]([C:24]4[N:32]([CH2:33][CH:34]5[CH2:36][CH2:35]5)[C:27]5=[N:28][CH:29]=[CH:30][CH:31]=[C:26]5[CH:25]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[C@H:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: COc1cc(C(=O)N2C[C@@H](NC(=O)OC(C)(C)C)CC[C@H]2C)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2C[C@@H](N)CC[C@H]2C)cc2nc(-c3cc4cccnc4n3CC3CC3)n(C)c12
Reaction time: 2.5 h
Yield: 90.2 %

Procedure:
To a flask containing tert-butyl((3S,6R)-1-(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-6-methylpiperidin-3-yl)carbamate (47 mg, 0.082 mmol) in dichloromethane (DCM) (1 mL) was added TFA (0.253 mL, 3.28 mmol) and the reaction was stirred for 2.5 h. The reaction mixture was concentrated in vacuo to afford a brown oil. This was dissolved in methanol and loaded onto an SCX cartridge (5 g). It was eluted with methanol (3 column volumes) and product eluted as free base with 2M ammonia in methanol. The filtrate from the ammonia fractions was concentrated in vacuo to yield a yellow oil—((2R,5S)-5-amino-2-methylpiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (35 mg, 0.074 mmol, 90% yield). The free base (35 mg) was dissolved in dichloromethane (DCM) (1 mL) in a vial and HCl (2M in Et2O) (0.037 mL, 0.074 mmol) was added. The resultant suspension was sonicated for 5 min and allowed to stand for 15 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].CN(C)CCCN=C=NCC.C(OCC)(=O)C>ClCCl>[CH2:19]1[C:20](=[O:21])[N:16]([O:13][C:12]([CH2:11][CH2:10][CH2:9][S:8][S:7][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:14])[C:17](=[O:22])[CH2:18]1
Reactant: O=C(O)CCCSSc1ccccn1
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCCSSc1ccccn1)ON1C(=O)CCC1=O
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Compound 11a (1.10 g, 4.8 mmol) and N-hydroxysuccinimide (0.64 g, 5.5 mmol) were dissolved in dichloromethane (50 mL). The solution was magnetically stirred as 1-[3-(dimethylamino)propyl]-3 ethylcarbodiimide (1.05 g, 5.5 mmol) was added. After 2 h, ethyl acetate (150 mL) was added and the solution was transferred to a separatory funnel and washed consecutively with 0.5 M HCl (30 mL) and saturated sodium chloride (20 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under vacuum. The residue was taken up in a minimum volume of ethyl acetate and was purified by silica chromatography using a mobile phase of hexanes:ethyl acetate:acetic acid (2.5:1:0.02, v/v/v). Fractions containing pure product were combined and solvent was removed to give N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB, 3a) (1.2 g, 76% yield). 1H NMR (CDCl3): δ 2.12-2.19 (2H, m), 2.78-2.87 (6H, m), 2.91 (2H, t, J=7.0), 7.06-7.12 (1H, m), 7.62-7.71 (2H, m), 8.48 (1H, d, 4.4 Hz). MS (M+Na+) Found: 348.8 Calculated: 349.4.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:4]([C:1](=[O:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]=1
Reactant: Brc1cccnc1
Reactant: CC(=O)Nc1ccccc1
Product: CC(=O)N(c1ccccc1)c1cccnc1
Yield: 101 %

Procedure:
Acetanilide (6.0 g) and 3-bromopyridine (14.1 g) were used to make a reaction in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane:=1:1 to 2:1) produced N-(3-pyridyl)-acetanilide (9.52 g, quantitative) as a pale red solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27]C)C>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:11]([NH:13][C:14]4[CH:15]=[CH:30][C:29]([N:26]([CH3:24])[CH3:27])=[CH:18][CH:19]=4)=[O:12])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)c1ccc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 34.7 mg (0.21 mmol) of 4-N,N-dimethylaminophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 21 mg (38.7% of theory) of the title compound are obtained.
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)N1.[CH3:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15]>C(N(CC)CC)C>[C:4]1([CH:9]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=1
Reactant: CC(=O)CC(C)=O
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)C=Cc1ccccc1

Procedure:
The title compound was prepared by the method of Example 6 (that is, using 2,2,6,6-tetramethylpiperidine as base instead of triethylamine) using 2,4-pentanedione instead of ethyl acetoacetate. The material prepared by this procedure was identical to that prepared by the method of Example 30, as indicated by the reverse phase chromatographic method described in Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH2:23][C:19]1[N:20]=[C:21]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=3)[C:6]([C:11]([OH:13])=[O:12])=[N:7]2)[CH:22]=[CH:17][N:18]=1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Reactant: Nc1nccc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To suspension of 6-bromo-1H-indazole-3-carboxylic acid (5 g, 20.77 mmol) in DMF (40 mL) was added NaH (60%, 1.7 g, 41.5 mmol). The mixture was stirred at RT for 10 min, followed by addition of 4-chloro-pyrimidin-2-ylamine (4.0 g, 31 mmol). The mixture was heated at 65° C. for 2 hr. The reaction cooled to RT, then another 1 eq NaH added (ca 0.78 g). Heating continued at 65° C. overnight. Reaction mixture was allowed to cool to RT. The mixture was quenched by portionwise addition to water (10 mL) resulting in formation of a precipitate. The mixture was acidified with 0.5M aq citric acid. The precipitate was collected by suction filtration through a fritted sinter funnel and washed with MeOH/EtOAc (1/1) and was thoroughly dried under high vacuum to give the title compound as a beige solid (5.8 g, LC-MS purity=88%); LC-MS: m/z=+333.85/335.80 (M+H)+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][C:9]=1[CH3:10].[C:14]1([S:20]([CH:23]=[C:24]2[CH2:27][O:26][CH2:25]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[CH3:10][C:9]1[CH:8]=[CH:7][C:6]([C:24]2([CH2:23][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH2:27][O:26][CH2:25]2)=[CH:5][C:4]=1[OH:3]
Reactant: O=S(=O)(C=C1COC1)c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(C2(CS(=O)(=O)c3ccccc3)COC2)cc1O
Reaction time: 0.02 h

Procedure:
A solution of KOH (1.5 M in water, 14.2 mL, 21.3 mmol) was added to a solution of [Rh(cod)C1]2 (0.525 g, 1.07 mmol) in dioxane (60 mL). The resulting yellow solution was stirred for 1 min. Then, 3-hydroxy-4-methylphenyl boronic acid (6.48 g, 42.6 mmol) and a solution of 3-((phenylsulfonyl)methylene)oxetane (4.48 g, 21.3 mmol) in dioxane (40 mL) were added in that order. After 1 h, a solution of KOH (1.5 M in water, 14.2 mL, 21.3 mmol) was added. After another 10 min, [Rh(cod)Cl]2 (0.525 g, 1.07 mmol) was added. The resulting mixture was stirred at room temperature overnight, and then partitioned between Et2O and aqueous NH4Cl. The aqueous layer was extracted with Et2O (3×). (During extractions, some solids crashed out in the organic layer, but went back into solution over time). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The dark orange residue was purified by silica gel chromatography (30-100% EtOAc/heptane) to provide 2-methyl-5-(3-((phenylsulfonyl)methyl)oxetan-3-yl)phenol. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.52-7.63 (m, 3 H) 7.41 (t, J=7.71 Hz, 2 H) 6.99 (d, J=7.83 Hz, 1 H) 6.57 (dd, J=7.83, 1.77 Hz, 1 H) 6.50 (d, J=2.02 Hz, 1 H) 4.99 (d, J=6.57 Hz, 2 H) 4.91 (d, J=6.57 Hz, 2 H) 4.03 (s, 2 H) 2.20 (s, 3 H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](Br)[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CS(C)=O>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([S:33]([CH3:32])(=[O:35])=[O:34])[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)[O-]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(Br)c3)c(=O)c2cc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(S(C)(=O)=O)c3)c(=O)c2cc1F

Procedure:
To a slolution of [2-(3-bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (10 mg, 0.02 mmol) in DMSO 0.5 ml, sodium methanesulfinate (62 mg, 0.06 mmol) was added. The reaction mixture was subjected to microwave irradiation (temperature 12° C.) for 45 seconds. A precipitate was formed and collected by filtration to give [7-fluoro-2-(3-methanesulfonyl-4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[CH2:1]([C@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: O=C(O)[C@H](CCO)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H](CCO)Cc1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-benzyl-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-benzyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:3][CH2:2]1.O.[NH2:25][NH2:26]>C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:25][N:26]=3)=[CH:9][C:8]=2[N+:21]([O-:23])=[O:22])[CH2:3][CH2:2]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(N2CCOCC2)c([N+](=O)[O-])c1

Procedure:
A mixture of 12.2 parts of 4(4-morpholino-3-nitrophenyl)-4-oxo-3-methylbutanoic acid, 3.8 parts of hydrazine hydrate in 50 parts by volume of absolute ethanol is heated at reflux for 4 hours, cooled and filtered. The solid product is collected, washed with hexane and dried at 80° C. under vacuum to give 6-(4-morpholino-3-nitrophenyl)-4,5-dihydro-5-methyl-3(2H)pyridazinone melting at 223°-225° C. Recrystallisation from a mixture of ethanol and dimethylformamide raises the melting point to 225°-227° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[CH:22]=[C:21]([Cl:23])[C:18]([C:19]#[N:20])=[C:17](Br)[C:16]=3[O:25][CH2:26][CH3:27])[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:28][N:29]([CH3:41])[C:30]([C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].O.ClCCl>>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:13]([C:15]3[C:16]([O:25][CH2:26][CH3:27])=[C:17]([C:35]4[CH:34]=[CH:33][C:32]([C:30]([N:29]([CH3:41])[CH3:28])=[O:31])=[N:37][CH:36]=4)[C:18]([C:19]#[N:20])=[C:21]([Cl:23])[CH:22]=3)[CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C#N)c1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 24.1 %

Procedure:
To a mixture of 4-[1-(4-amino-5-oxopyrido[2,3-d]pyrimidin-8(5H)-yl)ethyl]-2-bromo-6-chloro-3-ethoxybenzonitrile (20 mg, 0.04 mmol) and {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (13 mg, 0.069 mmol) in acetonitrile (2 mL, 40 mmol) was added sodium carbonate (10 mg, 0.09 mmol) in water (0.5 mL, 30 mmol). The reaction was degassed with bubbling nitrogen. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2 mg, 0.002 mmol) was added and degassed more with N2. Reaction was heated at 100° C. for 1 h. The crude product was purified on preparative LC-MS (acetonitrile, water, TFA) to give the desired product (0.005 g, 20%) as white amorphous solid. The product was isolated as a racemic mixture. LCMS calculated for C26H24ClN7O3(M+H)+: m/z=518.1; found: 518.1.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([OH:31])[C:29]#[CH:30]>C(NCC)C.[Cu]I.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>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:30]#[C:29][CH2:28][OH:31])=[CH:12][CH:13]=2)[C:8](=[O:16])[C:7]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCO
Reactant: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CC(C)(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred slurry of 1.15 g of 1-(tert-butyl)-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 10, 156 mg of copper (I) iodide, and 66 mg of dichlorobis(triphenylphosphine)palladium (II) in 23 mL of diethylamine, under argon, is added 0.16 mL of propargyl alcohol. The mixture is stirred for 18 hour at room temperature, then concentrated under reduced pressure. The residue is partitioned between water and chloroform-methanol, and the organic phase dried (MgSO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 2-4% methanol in dichloromethane affords 977 mg of tan solid. Recrystallization from ethanol provides 850 mg of the title compound as a beige solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C(P(CCCC)CCCC)CCC.[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][CH:37]=[C:38]2[NH:41][C:42](=[O:55])[CH2:43][N:44]([CH2:52][CH2:53]O)[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:33][CH:32]=1>O1CCCC1>[C:48]([O:47][C:45]([N:44]1[CH2:52][CH2:53][N:41]([C:38]2[C:39]3[C:34](=[CH:33][CH:32]=[C:31]([OH:30])[CH:40]=3)[CH:35]=[CH:36][CH:37]=2)[C:42](=[O:55])[CH2:43]1)=[O:46])([CH3:49])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(=O)Nc1cccc2ccc(O)cc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3ccc(O)cc23)C(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of di-tert-butylazodicarboxylate (10.81 g, 43.2 mmol) in 60 mL of tetrahydrofuran at 0° C. was added tributylphosphine (10.76 mL, 43.2 mmol) dropwise. After 10 minutes, a solution of the crude product from Step B (ca. 28.8 mmol) in 30 mL of tetrahydrofuran was added dropwise, and the reaction was allowed to warm to room temperature. After two hours, HPLC analysis showed partial conversion. The solution was cooled to 0° C., and additional portions of tributylphosphine (3.0 mL, 18 mmol) and di-tert-butylazodicarboxylate (4.6 g, 18 mmol) were added. The reaction was warmed to room temperature, and stirred for 16 hours. The solution was concentrated in vacuo, and the resulting product was purified by isilica gel chromatography (0-5% MeOH/CH2Cl2) to provide the titled product as a dark brown foam, contaminated with tributylphosphine oxide impurity. This material was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:22]([O:32]C(=O)C)=[CH:21][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH2:1]([C:3]1[CH:24]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:22]([OH:32])=[CH:21][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OC(C)=O)cc1OCCCOc1ccccc1/C=C/C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1/C=C/C(=O)O
Reaction time: 8 h
Yield: 72.2 %

Procedure:
3-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-acetoxyphenoxy)propoxy)phenyl)-E-propenoic acid (90 mg, 0.2 mmol) was dissolved in methanol (10 mL). 0.1M Aqueous potassium carbonate solution was added and the solution stirred under nitrogen overnight. The thin-layer chromatogram showed a single spot of the same Rf as the starting material so additional 1.0M potassium carbonate solution was added and the solution stirred for a further 4 hours. The reaction mixture was poured into 1M hydrochloric acid (50 mL) and the mixture extracted 3 times with chloroform. The combined chloroform extracts were dried with magnesium sulfate and evaporated to provide 63 mg of the title intermediate as an oil which solidified to a glass. MS, NMR.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CCCNC1
Solvent: ClCCl
Product: CC(=O)N1CCCC(O)C1
Temperature: 10 °C

Procedure:
3-Hydroxypiperidine (0.4 mole) is dissolved in 150 ml. of methylene chloride. The solution is cooled to 10° C. and acetic anhydride (0.46 mole) is added dropwise, maintaining the temperature under 20° C. The reaction mixture is allowed to come to room temperature, and is then refluxed for 2 hours. The methylene chloride is evaporated off, and the remaining liquid is distilled under high vacuum. A thick yellow oil is collected at 122°-126° C. (0.3 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C@H:12]2[C@H:17]([O:18]CC3C=CC=CC=3)[C@@H:16]([O:26]CC3C=CC=CC=3)[C@H:15]([O:34]CC3C=CC=CC=3)[C@@H:14]([CH2:42][O:43]CC3C=CC=CC=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[C:5]([C@H:12]2[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([OH:34])[C@@H:14]([CH2:42][OH:43])[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCCO3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCCO3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of compound 86 (509 mg, 0.615 mmol) in THF/MeOH (10 mL/10 mL) was added 10% Pd/C (77 mg) at r.t. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound E013 (75 mg, 10%).