Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH2:16][C:17]([OH:19])=O)[CH:7]=[CH:6]2.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:15])[C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([CH2:16][C:17]([Cl:22])=[O:19])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(CC(=O)O)cc2c(C)c1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc2ccc(CC(=O)Cl)cc2c(C)c1OC

Procedure:
A mixture of 24.0 g. of 6,7-dimethoxy-8-methyl-2-naphthaleneacetic acid and 30 ml. of thionyl chloride in 250 ml. of benzene was kept at 40° C. one hour and then overnight at room temperature. The reaction mixture was then evaporated to dryness in vacuo at 50° C. Additional benzene was added and evaporation repeated to give 6,7-dimethoxy-8-methyl-2-naphthaleneacetyl chloride. An infrared spectrum indicated no remaining carboxylic acid and this material was used directly in the preparation of 6,7-dimethoxy-8-methyl-2-naphthaleneacetamide as described hereinabove in Example 98.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(CCl)N1CCN(c2ccc(O)cc2)CC1
Solvent: CO
Product: O=C(CN1CCOCC1)N1CCN(c2ccc(O)cc2)CC1
Temperature: 50 °C

Procedure:
A mixture of 10 parts of 1-(2-chloroacetyl)-4-(4-hydroxyphenyl)piperazine, 6.9 parts of morpholine and 40 parts of methanol is stirred and heated for 2 hours at 50° C. The reaction mixture is evaporated and the residue is stirred with water. The precipitated product is filtered off, dried on the filter and crystallized from 2-propanol, yielding 5.5 parts of 1-(4-hydroxyphenyl)-4-[(4-morpholinyl)acetyl]piperazine; mp. 197.3° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([N:15]=[C:16]=[O:17])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:16](=[O:17])[NH:15][C:13]1[CH:14]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([C:21]([F:22])([F:23])[F:24])=[C:2]([Cl:1])[CH:7]=2)[CH:10]=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C=Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-2-nitrophenyl isocyanate (107 g, 0.299 mol) in methylene chloride is cooled to 0° C., treated with a mixture of glycine ethyl ester hydrochloride (50.1 g, 0.359 mol) and triethylamine (166 mL, 1.20 mol) in methylene chloride over 10 minutes, refluxed overnight, cooled to room temperature, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. A solution of the solid in methylene chloride is placed on a silica gel plug, eluted with methylene chloride and concentrated in vacuo to give the title product as a yellow solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1>>[CH:1]1([NH:4][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:22][CH2:21]2)[CH2:3][CH2:2]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CCC(NC2CC2)CC1

Procedure:
Cyclopropylamine and sodium triacetoxy borohydride were added to a 1,2-dichloromethane solution of benzyl 4-oxopiperidine-1-carboxylate to obtain benzyl 4-(cyclopropylamino)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Combine 2-(2-(5-amino-1H-indol-3-yl)ethyl)isoindole-1,3-dione (0.5 g, 1.64 mmol) and 4-dimethylaminopyridine (0.3 g, 2.5 mmol) and dissolve in 30 mL dichloromethane and cool to 0° C. Treat the reaction mixture with benzoyl chloride (276 mg, 1.96 mmol) and stir overnight during which the temperature was allowed to warm to room temperature. Concentrate to residue and chromatograph the residue on silica gel eluting with 0.5% MeOH in CHCl3 to give the title compound as a solid: ISMS 410 (M+1); 1H NMR (CDCl3) 7.86–7.85 (m, 2H), 7.79 (s, 1H), 7.72–7.68 (m, 2H), 7.60–7.57 (m, 2H), 7.46–7.42 (m, 1H), 7.4–7.36 (m, 3H), 7.13–7.11 (d, 1H), 6.89–6.88 (m, 1H), 3.88–3.84 (t, 2H), 3.00–2.97 (t, 2H).
Reaction SMILES: [OH-].[Li+].C([O:6][CH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[N:11]=[N:10][N:9]=1)(=O)C>C(O)C.O>[F:22][C:19]([F:20])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]([CH2:7][OH:6])=[N:9][N:10]=[N:11]2)=[N:14][CH:15]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Lithium hydroxide (0.30 g, 12.5 mmol) was added at 0° C. to a solution of {1-[5-(trifluoromethyl)-2-pyridinyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 57, 1.80 g, 6.27 mmol) in a mixture of ethanol and water (2:1). The reaction mixture was stirred for 3 hr at room temperature. The ethanol was removed under reduced pressure. The residue was diluted with DCM and washed with ice-water, saturated NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 30% ethyl acetate/pet ether, to give the title compound (0.90 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([CH3:18])[N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[C:10]([CH3:18])[N+:9]=2[O-:27])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(C)nc1-c1ccc(F)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)[n+]([O-])c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl 2-(4-fluorophenyl)-6-methylpyridin-3-carboxylate (17.3 g) was dissolved in dichloromethane (600 ml), the solution cooled to 0° C. and MCPBA (24.3 g) added in portions over 25 minutes. The solution was then warmed to ambient temperature and stirred for 16 hours washed with saturated aqueous sodium bicarbonate (500 ml), dried and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with methanol/ethyl acetate (1:12) to give 2-(4-fluorophenyl)-3-(methoxycarbonyl)-6-methylpyridine-1-oxide as a pale yellow oil which crystallised on standing (18.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH2:9])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc([N+](=O)[O-])cc1
Yield: 86.3 %

Procedure:
2-(4-Nitrobenzyl)isoindoline-1,3-dione (1.4 g, 4.96 mmol) was dissolved in tetrahydrofuran (8 mL). To the solution hydrazine monohydrate (1.48 mL, 19.84 mmol) and p-toluenesulfonic acid monohydrate (94 mg, 0.5 mmol) was added. It was refluxed for 6 h. TLC showed complete consumption of starting material. The mixture was extracted with ethyl acetate and washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give (4-nitrophenyl)methanamine (651 mg, 86%).
Reaction SMILES: Cl.[F:2][C:3]1([F:30])[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23](=[O:24])[C:22]4[C:21]([C:25](O)=[O:26])=[CH:20][C:19]([F:28])=[CH:18][C:17]=4[CH:16]3[CH3:29])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C[N:32](C)C=O.C(N(CC)C(C)C)(C)C>>[F:2][C:3]1([F:30])[CH2:4][CH2:5][CH:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:23](=[O:24])[C:22]4[C:21]([C:25]([NH2:32])=[O:26])=[CH:20][C:19]([F:28])=[CH:18][C:17]=4[CH:16]3[CH3:29])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: CN(C)C=O
Reactant: CC1c2cc(F)cc(C(=O)O)c2C(=O)N1C1CCN(C2CCC(F)(F)CC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2cc(F)cc(C(N)=O)c2C(=O)N1C1CCN(C2CCC(F)(F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylic acid hydrochloride (80 mg, 0.2 mmol) in N,N-dimethylformamide (2 mL) hydroxybenzotriazole ammonium salt (61 mg, 0.4 mmol), 1-ethyl-3-(3′-dimethylamino) carbodiimide hydrochloric acid salt (77 mg, 0.4 mmol) and N,N-diisopropylethylamine (0.14 mL, 1 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduce pressure and the residue was dissolved in ethyl acetate. The solution was washed twice with sodium carbonate saturated aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography (dichloromethane/methanol 96:4) to afford the title compound (60 mg, 73%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>C(COC)OC.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichoride (842 mg, 1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 hours and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by column chromatography to yield 6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic acid methyl ester (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3): δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:3]=1.[NH2:22][C:23]1(B2OC(C)(C)C(C)(C)O2)[N:28]=[CH:27][CH:26]=[CH:25][NH:24]1>>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[N:7]=[C:6]3[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]3=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:3]=2)=[CH:25][N:24]=1
Reactant: CC1(C)OB(C2(N)N=CC=CN2)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2c(C)nn3C)c1
Product: COc1cccc(Nc2nc(-c3cnc(N)nc3)nc3c2c(C)nn3C)c1

Procedure:
(6-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(3-methoxy-phenyl)-amine was reacted with 2-amino-pyrimidine boronic acid pinacol ester using General Procedure A to give 118. NMR (CDCl3): 2.74 (3H, s), 3.90 (3H, s), 4.04 (3H, s), 5.28 (2H, br), 6.76 (1H, d), 6.99 (1H, br), 7.35 (1H, d), 7.34 (1H, t), 7.55 (1H, s), 9.38 (2H, s). MS: MH+ 363.22 (25%)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.O1CCCC1.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[Cl:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g), tetrahydrofuran (50 mL) and toluene (50 mL) was added a solution (5 mL) of thionyl chloride (1.5 mL) in toluene under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give colorless crystals (4.50 g, 94%) of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole. melting point: 100-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: COc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-methoxy-phenyl)-pyrazolo[1,5-a]pyrimidine (202 mg, 0.688 mM), then morpholine (120 μL, 1.38 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined together and then dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to give the title compound (235 mg, yield: 99%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1([C:7]2([CH2:10][CH2:11][O:12][S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C2(CCO)CC2)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(C3(C)OCCO3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
470 mg of 9 is dissolved in 10 ml of pyridine, and p-toluenesulfonyl chloride is added at 0° C. under nitrogen. It is stirred for 1 hour at 0° C., and then sodium bicarbonate solution is added. It is extracted with ethyl acetate, washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried on sodium sulfate and concentrated by evaporation. After the residue is chromatographed on silica gel with ethyl acetate/hexane, 670 mg of the title compound remains as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[CH:30]=[O:31]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Dissolve tert-butyl 4-chloropyridin-2-ylcarbamate (1.95 g, 0.00855 moles) in dry THF (50 mL) and cool to −78° C. under nitrogen atmosphere. Add dropwise 1.6 M n-BuLi/hexane (12.8 mL, 0.02053 moles) over a period of 15 minutes while maintaining the reaction temperature below −70° C. Stir the resulting red orange solution at −78° C. for 2 hours. Add DMF (3.3 mL, 0.04275 moles) dropwise to the reaction mixture while maintaining the reaction temperature below −70° C. Stir further at −78° C. for 2 hours and then quench the reaction mixture with saturated ammonium chloride (50 mL). Warm the reaction mixture to room temperature, extract with EtOAc (3×50 mL) and dry with MgSO4. Filter and concentrate under reduced pressure to afford a yellow viscous oil. Purify the crude product by flash column chromatography using 15-20% EtOAc/hexane to afford the title product as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20]([B:23]3[NH:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:32]5[CH:33]=[CH:34][CH:35]=[C:25]([C:26]=45)[NH:24]3)=[CH:19][CH:18]=2)O1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:24]1[C:25]2=[CH:35][CH:34]=[CH:33][C:32]3=[CH:31][CH:30]=[CH:29][C:27](=[C:26]23)[NH:28][B:23]1[C:20]1[CH:19]=[CH:18][C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(B3Nc4cccc5cccc(c45)N3)cc2)OC1(C)C
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(B2Nc3cccc4cccc(c34)N2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (57.7 mg) was added to a suspension of 3-bromopyridin-2-amine (432 mg), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (1016 mg) and sodium carbonate decahydrate (1429 mg) in DME (10 mL) and water (2 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr and at 70° C. overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (397 mg) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH2:9]1[CH2:15][S:12](=O)(=[O:13])[O:11][CH2:10]1>C(OCC)(=O)C>[S:12](=[CH:15][CH2:9][CH2:10][N:3]1[CH:4]=[C:5]([CH3:8])[N:6]=[CH:7][CH:2]1[CH3:1])(=[O:13])=[O:11]
Reactant: Cc1cnc(C)cn1
Reactant: O=S1(=O)CCCO1
Solvent: CCOC(C)=O
Product: CC1=CN(CCC=S(=O)=O)C(C)C=N1
Temperature: 40 °C

Procedure:
6.0 g of 2,5-dimethylpyrazine (701) and 7.0 g of 1,3-propane sultone were dissolved in 10 ml of ethyl acetate and heated at 40° C. for 2 days. The resultant solid was then filtered and washed with ethyl acetate giving 7.9 g of product (700). It was recrystallized from propanol/water, m.p. 258°-9°. UV H2O max: 204 (3.94), 290 (3.85). 13C NMR: 159.25, S (C5); 152.47, D (C3); 146.91, S (C2); 136.88, D (C6); 57.84, T (NCH2); 47.94, T (CH2SO3-); 25.42, T (CH2); 21.49, Q, 17.16, Q (ArCH3). 1H NMR: 9.15, S (H3); 8.83, S (H6); 4.77, T (NCH2); 3.09, T (CH2SO3-), 2.90, S, 2.75, S (ArCH3); 2.40, M=5 (--CH2 --).
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.[OH-].[Na+]>C1COCC1>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 74.1 %

Procedure:
The hydrolysis conditions described for 191 were employed. Thus, ethyl 4-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)butanoate (217) (0.155 g, 0.39 mmol) was dissolved in THF and EtOH (1:1, 10 mL) and then treated with 1 N NaOH (2 ml) at 70° C. for 1 h. Upon acidification, work-up, and purification afforded 0.110 g (74%) of the title compound 218. 1H NMR (300 MHz, CD3OD): δ 7.02 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.1 Hz, 2H), 4.00 (t, J=6.3 Hz, 2H), 2.49 (t, J=7.5 Hz, 2H), 2.31 (br s, 4H), 2.05 (quintet, J1=13.5 Hz, J2=6.9 Hz, 2H), 1.60 (s, 8H). LCMS (ESI): m/z 379 (M−H)−. Anal. Calcd for C24H28O4, C, 75.46; H, 7.42; Found: C, 75.81, H, 7.64.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:58])[C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][C:34]=2[F:35])[C:31]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[C:4]([F:58])[C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:59](=[O:60])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:23])=[C:34]([F:35])[CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:41])([CH3:40])[CH3:42]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2cc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3cc2F)C(=O)N(C)Cc2cc(N)cc(F)c2S(=O)(=O)C2CC2)ccc1[C@@H](C)CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1cc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2cc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
A solution of 29A (133 mg, 0.161 mmol) in acetonitrile (3 mL) and dichloromethane (6 mL) was cooled to 0° C. To this solution was added phosgene (20% in toluene, 0.088 mL, 0.178 mmol). The mixture was stirred at 0° C. for 5 min, and rt for 1 h. The mixture was bubbled with Ar for 10 min to remove excess phosgene. The resulting solution was added dropwise over 3 h via a syringe pump into a solution of TEA (0.225 mL, 1.614 mmol) in CH2Cl2 (260 mL). The solution was stirred for 16 h, concentrated and purified by flash chromatography to give a mixture of diastereoisomers (96 mg, 0.113 mmol, 70.0% yield). The diastereoisomers were separated by a prep chiral HPLC equipped with a IA column to give 29B (44 mg, 0.052 mmol, 46.3% yield). MS (ESI) m/z: 850.2 [M+1]+. 1H NMR (500 MHz, methanol-d4) δ ppm 8.09 (1H, d, J=5.8 Hz), 7.77 (1H, d, J=7.7 Hz), 7.53 (1H, d, J=6.1 Hz), 7.50 (1H, d, J=8.0 Hz), 7.42 (1H, d, J=11.8 Hz), 7.00-7.09 (2H, m), 6.61 (2H, dd, J=12.1, 1.9 Hz), 6.24 (1H, s), 5.76 (1H, d, J=17.9 Hz), 5.72 (1H, t, J=2.9 Hz), 4.62 (1H, t, J=11.1 Hz), 4.21 (1H, d, J=17.9 Hz), 3.96 (1H, dd, J=10.6, 4.3 Hz), 3.47 (1H, ddd, J=11.4, 7.0, 4.4 Hz), 3.32-3.38 (3H, m), 2.97 (1H, dd, J=4.8, 3.2 Hz), 2.22-2.33 (3H, m), 1.25-1.37 (24H, m), 1.03-1.13 (2H, m).