Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.[F-].[Cs+].C(#N)C>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[N:5]=[C:6]([C:21]2[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:7]=1[F:8]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: COC(=O)c1nc(-c2ccc(OC)nc2)c(F)c(N)c1OC
Temperature: 85 °C
Yield: 28.4 %

Procedure:
To a tube, methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (500 mg, 2.131 mmol), (6-methoxypyridin-3-yl)boronic acid (391 mg, 2.56 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (78 mg, 0.107 mmol) and Cesium Fluoride (647 mg, 4.26 mmol) were charged as solids. The tube was sealed and charged with inert atmosphere. The solids were then diluted with Dioxane (5700 μl) and Water (1400 μl). The resulting suspension was heated to 85° C. for 18 hrs. The reaction solution was poured in to a brine solution. The aqueous phase was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The product was purified (flash chromatography: silica, 5-50% EtOAc in Hex 16 CV; C18 5-100% ACN in H2O 16 CV) to yield methyl 4-amino-3-fluoro-5,6′-dimethoxy-[2,3′-bipyridine]-6-carboxylate (186 mg, 0.605 mmol, 28.4% yield). ESIMS for m/z 308 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 3.86 (s, 3H), 3.92 (s, 3H), 6.53 (s, 2H), 6.95 (dd, J=8.6, 0.8 Hz, 1H), 8.10 (ddd, J=8.6, 2.4, 1.1 Hz, 1H), 8.58 (t, J=2.0 Hz, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.20.
Reaction SMILES: C([C@:18]([NH2:31])([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:19]([OH:21])=O)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:47]1([C:53]2([C:59](=[O:63])[CH2:60][CH2:61][CH3:62])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C.CN(C)C=O>[NH2:31][C@@H:18]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[C:19]([N:56]1[CH2:57][CH2:58][C:53]([C:59](=[O:63])[CH2:60][CH2:61][CH3:62])([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:54][CH2:55]1)=[O:21]
Reactant: COc1ccc(C[C@](N)(C(=O)O)C(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reactant: CCCC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCC(=O)C1(c2ccccc2)CCN(C(=O)[C@@H](N)Cc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution containing 11.9 g (28.5 mmol) of (S)-2-Fmoc-amino-3-(4-methoxy-phenyl)propionic acid dissolved in 120 mL of dichloromethane and 10 mL of dimethylformamide are added 5.51 g (38.9 mmol) of EDC and 5.25 g (38.9 mmol) of HOBt. After stirring for 30 minutes at room temperature, a solution of 6.95 g (26.1 mmol) of 1-(4-phenylpiperidin-4-yl)-butan-1-one hydrochloride and 18 mL of triethylamine in 150 mL of dichloromethane is added. The reaction medium is stirred for 2 hours, and saturated aqueous sodium hydrogen carbonate solution is then added. The organic compounds are extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then filtered, and the solvents are evaporated off. The crude product is chromatographed on silica gel (eluent: 9/1 dichloromethane/methanol). 4.7 g of 1-{1-[(S)-2-amino-3-(4-methoxyphenyl)-propionyl]-4-phenylpiperidin-4-yl}butan-1-one in the form of an orange oil are obtained in a yield of 44%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:38](=[O:40])[CH3:39])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: CN1CCC(NCCOc2cccc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Product: CC(=O)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C1CCN(C)CC1
Yield: 41 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(1-methylpiperidin-4-yl)amino]ethoxy}quinazolin-4-amine and acetyl chloride to give the title compound in 41% yield; NMR spectrum (DMSO-d6) 1.62-1.90 (m, 4H), 2.09 (s, 3H), 2.15-2.43 (m, 4H), 2.79-3.13 (m, 3H), 3.76-3.83 (m, 2H), 3.86-3.92 (m, 1H), 4.30-4.47 (m, 2H), 5.31 (s, 2H), 7.21 (d, 1H), 7.26 (d, 1H), 7.32-7.40 (m, 2H), 7.57-7.61 (m, 2H), 7.69-7.75 (m, 1H), 7.86-7.92 (m, 1H), 7.98-8.00 (m, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.95 (s, 1H); Mass spectrum MH+ 561.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.O>CC(CC)=O>[CH3:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CNC(=O)C=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
195 mg (1.1 mmol) 3-(4-hydroxy-phenyl)-N-methyl-acrylamide is dissolved in 25 ml ethyl methyl ketone and 304 mg (2.2 mmol) potassium carbonate is added, followed by 289 mg (1.2 mmol) of 4-(trifluoromethyl)benzyl bromide. The reaction mixture is stirred overnight at RT, heated to 50° C. for 3 hours, treated with water and extracted 3 times with dichloromethane. The extract is dried over magnesium sulfate, concentrated and treated with ether to yield 260 mg (70%) of a colorless solid. MS: m/e=336.1 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3]1=[O:11].C[O-].[Na+].Cl.Cl[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]1=[O:11]
Reactant: Cn1c(=O)[nH]c2ccccc21
Reactant: ClCc1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)n(Cc2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A mixture of 25 parts of 1,3-dihydro-1-methyl-2H-benzimidazol-2-one, 64 parts of sodium methanolate solution 30% and 240 parts of methanol is stirred for one hour at room temperature. Then there are added 27.88 parts of 3-(chloromethyl)pyridine hydrochloride and stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and the formed precipitate (sodium chloride) is filtered off. The filtrate is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 16 parts (39.3%) of 1,3-dihydro-1-methyl-3-(3-pyridinylmethyl)-2H-benzimidazol-2-one; mp. 90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH:10]=1.COC1C=CC=CC=1C1CCC(=O)C=C1>[Pd].C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1
Reactant: COc1ccccc1C1=CCC(=O)CC1
Agent: [Pd]
Agent: COc1ccccc1C1C=CC(=O)CC1
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCC(=O)CC1
Reaction time: 6.5 h

Procedure:
To a suspension of palladium on carbon (3.75 g, 25% wt) in 200 mL ethylacetate was added a 1:2 mixture of 4-(2-Methoxy-phenyl)-cyclohex-3-enone and 4-(2-Methoxy-phenyl)-cyclohex-2-enone (15 g, 75.0 mmol) under argon. The suspension was stirred under a hydrogen at 1 atm. for 6.5 h, filtered through celite, concentrated in vacuo, and crystallized from ethylacetate to give 4-(2-Methoxy-phenyl)-cyclohexanone.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].C[Mg]Br.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[C:8]12([N:7]3[C:5](=[O:6])[C:4]([CH2:25][C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)([CH2:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[C:3]3=[O:2])[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2
Reactant: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1N(C23CC4CC(CC(C4)C2)C3)C(=O)C1(Cc1ccncc1)Cc1ccncc1
Temperature: 50 °C
Yield: 21.7 %

Procedure:
To a solution of N-adamantan-1-yl-2,2-bis-pyridin4-ylmethyl-malonamic acid methyl ester (100 mg, 0.23 mmol) in anhydrous tetrahydrofuran (1.5 ml), a 1.4M solution of methyl magnesium bromide in toluene/ tetrahydrofuran (Aldrich Chemical Co., 330 μl, 0.46 mmol of methyl magnesium bromide) and cuprous bromide (1.6 mg) was added. The reaction was heated at 50° C. for 6 hours and then quenched by addition to 15 ml of ice water containing 200 μl of concentrated sulfuric acid. The pH of the mixture was then adjusted to 8.0 with aqueous sodium bicarbonate. Two 15 ml methylene chloride extractions were combined, dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil (104 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with methanol/methylene chloride=4:96 in volume) afforded the title compound (20 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]([CH2:14][CH2:15][CH2:16][N:17]([CH3:35])[CH2:18][CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:34])[C:3]1=[O:36].[Na].[CH2:39](I)[CH3:40]>C(O)C>[CH3:1][C:2]1([CH3:37])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:39][CH3:40])=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]([CH2:14][CH2:15][CH2:16][N:17]([CH3:35])[CH2:18][CH2:19][CH2:20][N:21]2[C:30](=[O:31])[C:29]([CH3:32])([CH3:33])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:34])[C:3]1=[O:36]
Reactant: CCI
Reactant: CN(CCCN1C(=O)c2ccccc2C(C)(C)C1=O)CCCN1C(=O)c2cc(O)ccc2C(C)(C)C1=O
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc2c(c1)C(=O)N(CCCN(C)CCCN1C(=O)c3ccccc3C(C)(C)C1=O)C(=O)C2(C)C

Procedure:
1.3 gm of N-[3-(3,4-dihydro-4,4-dimethyl-7-hydroxy-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-N-[3-(3,4-dihydro-4,4-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)-propyl]-methylamine were dissolved in 10 ml of absolute ethanol, the resulting solution was added to a solution of 0.06 gm of sodium in 10 ml of absolute ethanol, and 0.42 gm of ethyl iodide was added to the mixed solution. The mixture was refluxed for 30 minutes, another 0.42 gm of ethyl iodide was added, and the mixture was refluxed again for 30 minutes. The product was purified on a silicagel column (eluant: chloroform/ethanol = 25:1), and the hydrochloride was precipitated from acetone with ethereal hydrochloric acid. The hydrochloride sintered above 45° C; yield: 0.5 gm (35% of theory).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[SH:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:25][CH2:24][CH2:23][S:22][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: OCCS
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccc(SCCO)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoronaphthacene-5,12-dione (prepared according to U.S. Pat. No. 4,522,754), 0.31 g (3.98 mmol) of 2-mercaptoethanol, 1.50 g (10.86 mmol) of potassium carbonate and 10 ml of DMSO are stirred at 25° C. for 3 minutes. The mixture is poured into water. The crystals are filtered off and dissolved in tetrahydrofuran/toluene, the solution dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield 1 g (83%); melting point 195°-196° C.
Reaction SMILES: O[NH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>[Ni].COCCO>[NH2:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Agent: [Ni]
Solvent: COCCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 80 °C

Procedure:
To 100 parts of ethyleneglycol monomethyl ether (so called methyl-Cellosolve) there were added 5.0 parts of 1-hydroxylaminoanthraquinone and 0.25 part of Raney nickel. The reaction mixture was heated to 80°C over 30 minutes and maintained at 80°C for 4 hours, with stirring, while introducing thereinto 0.04 parts/hour of gaseous hydrogen. The reaction mixture was then purged of gaseous hydrogen with gaseous nitrogen, heated to 100°C and filtered while hot to separate the catalyst as residue. The filtrate was, while maintained at 80°C, added with 100 parts of water, with stirring, to precipitate crystals. The slurry thus formed was then cooled to room temperature and filtered. The residue was washed with 5 parts of methanol and dried to obtain 4.2 parts of 1-aminoanthraquinone of a purity of 97 %. In the filtrate there remained 0.1 part of 1-aminoanthraquinone dissolved.
Reaction SMILES: [CH3:1][O:2][NH2:3].[N:4]([C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[C:5]=[O:6]>>[CH3:1][O:2][NH:3][C:5]([NH:4][C:7]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[O:9][N:8]=1)=[O:6]
Reactant: CON
Reactant: CC(C)(C)c1cc(N=C=O)no1
Product: CONC(=O)Nc1cc(C(C)(C)C)on1

Procedure:
8.5 g of methoxyamine was added slowly to a stirred solution of 15 g of 3A in 600 ml of tetrahydrfuran. The resulting mixture was filtered and the solid was triturated with ether to give 1-methoxy-3-(5-(1,1-dimethylethyl)-isoxazol-3-yl)urea (3B), m.p.: 145°-148° C.
Reaction SMILES: C(OC(=O)C(Cl)C(=O)C)C.C([O-])=O.[NH4+].C([O-])([O-])=O.[Na+].[Na+].C([O:23][C:24]([C:26]1[O:30][CH:29]=[N:28][C:27]=1[CH3:31])=[O:25])C.Cl>C(O)=O.O.[OH-].[Na+]>[CH3:31][C:27]1[N:28]=[CH:29][O:30][C:26]=1[C:24]([OH:25])=[O:23]
Reactant: CCOC(=O)c1ocnc1C
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O=CO
Solvent: O
Product: Cc1ncoc1C(=O)O
Temperature: 25 °C

Procedure:
A solution of 40.0 grams (0.243 mol, 1.0 eq) of 2-Chloro-3-oxo-butyric acid ethyl ester in 240 mL formic acid (99%) was stirred at room temperature in a 500 mL round bottom flask equipped with a H2O condenser. To this solution was added 80.0 grams (1.27 mmol, 5.2 eq) of ammonium formate. The solution was then heated to reflux for five hours. After cooling to room temperature, the solution was diluted with water (1 L) and neutralized with Na2CO3. The aqueous solution was then extracted three times with Et2O and the combined organic fractions were dried over MgSO4. After concentration, vacuum distillation (˜10 mmHg, b.p. 53° C.-61° C.) gave a mixture of starting material and 4-Methyl-oxazole-5-carboxylic acid ethyl ester as a colorless oil (21.7 grams). This mixture was dissolved in 100 mL of aqueous sodium hydroxide (2 N) and refluxed for 1 minute. The reaction was then poured onto ice and acidified with concentrated HCl and the known (Sen & Sengupta (1985) Ind. J. Chem. Section B: Org. Chem. Including Med. Chem. 24B(5):535-8) free acid precipitated as a white solid (6.04 grams, 20% overall yield) Mp: 241.4-242.6° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.CCCCCC.[OH:14][CH2:15][C:16]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([CH3:18])[CH3:17].B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:14][CH2:15][C:16]([NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([CH3:18])[CH3:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Agent: Cl
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: COCC(C)(C)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 2M trimethylsilyldiazomethane in hexane (3.9 ml, 7.8 mmol) was added dropwise to a solution of N-(2-hydroxy-1,1-dimethylethyl)-2,4-difluorobenzamide obtained in Example 27 (0.59 g, 2.6 mmol) and boron trifluoride diethyl etherate (43 mg, 0.3 mmol) in methylene chloride (6 ml), and stirred at room temperature overnight. To the reaction mixture was added 1N hydrochloric acid (5 ml) dropwise, and the resulting mixture was concentrated and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the title compound (0.38 g; 60%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C:18]2[C:23](Br)=[N:22][C:21]([Br:25])=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.C(OCC)(=O)C>[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C:18]2[C:23]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:22][C:21]([Br:25])=[CH:20][N:19]=2)(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: COCCO
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1ccc(Cl)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COCCOc1nc(Br)cnc1NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.17 h

Procedure:
2-Methoxyethanol (0.04 g) was added to a stirred suspension of sodium hydride (0.05 g of 60%) in 1,2-dimethoxyethane (5 mL). After 10 minutes, 5-chloro-N-(3,5-dibromo-2-pyrazinyl)-2-thiophenesulphonamide (0.2 g) was added. After 30 minutes, 5% aqueous citric acid and ethyl acetate were added. The organic layer was separated dried (MgSO4) and the solvent was evaporated. Chromatography on silica eluting with hexane/ethyl acetate gave the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=3[F:44])(=[O:36])=[O:35])[C:28]=2[F:45])[CH:5]=[CH:4][N:3]=1.[CH3:46][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:44][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=1[S:34]([NH:33][C:29]1[C:28]([F:45])=[C:27]([C:9]2[N:10]=[C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:46])[N:7]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (150 mg, 0.221 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (9.00 mg, 0.011 mmol) and dimethylzinc (0.221 mL, 0.441 mmol) were then added. The reaction mixture was stirred at 80° C. for 1 h. The reaction mixture was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to obtain the title compound (75 mg). MS (ESI): 660.5 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[CH:6]1[OH:16])[CH2:2][CH2:3][CH3:4].Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([C:5]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH:6]1[OH:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)CCc2c(O)cccc2C1O
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CCCC)CCc2c(OCc3ccc4ccccc4n3)cccc2C1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A mixture of (+)2,2-dibutyl-5-hydroxy-1,2,3,4-tetrahydro-1-naphtol(138mg), 2-chloromethylquinoline(89mg) and potassium carbonate(138mg) in N,N-dimethylformamide(1 ml) was stirred at 70° C. for 3 hours. The cooled mixture was poured into brine(10ml). The separated oil was extracted with brine(5 ml X 3). The combined organic layers were washed with brine(5 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by columnchromatography on silica gel(elution by 15% ethyl acetate in hexane) to give a pale yellow syrup. The residual syrup was crystallized from methanol to yield (+)-2,2-dibutyl-5-(2-quinolylmethoxy)-1,2,3,4-tetrahydro-1-naphtol(162 mg) as white solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:15]=3)[N:10]=[C:9]([C:18]#[N:19])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCCl
Reactant: N#Cc1nc(NC2CCCC2)c2cc(O)ccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc2nc(C#N)nc(NC3CCCC3)c2c1

Procedure:
4-Cyclopentylamino-6-hydroxy-quinazoline-2-carbonitrile (0.4 mmol), (2-Chloro-ethyl)-dimethyl-amine hydrochloride (0.55 mmol) and cesiumcarbonate (3.5 mmol) are stirred in DMF (3 ml) at RT for 20 hours. The suspension is filtered, washed with little DMF and water is added to the filtrate until the solution gets turbide. The precipitate formed is filtered off and dried (vacuum). A white powder with mp. 158-160° C., Rf=0.51 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)([OH:3])=[O:2].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:19][CH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:7]=1
Reactant: Cc1nc(CCC(=O)O)cs1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCc1csc(CBr)n1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a stirring solution of 4-carboxyethyl-2-methyl thiazole (30.3 g) in CCl4 (1 L) was added NBS (37.7 g) and AIBN (2.2 g). The resulting mixture was refluxed and irradiated with UV light for 4 hours. The mixture was cooled to room temperature and filtered. The solution was flash chromatographed (CH2Cl2) to yield 36.6 g of a red oil. This material was used without further purification.