Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:22][N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH2:8])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: OB(O)c1ccccc1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCC(Nc2cc(N)ncc2-c2ccccc2)CC1
Temperature: 130 °C
Yield: 238.6 %

Procedure:
A solution of the N-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (Synthesis 153-C) (0.187 g, 0.57 mmol), phenyl boronic acid (0.140 g, 1.15 mmol), sodium carbonate (0.153 g, 1.43 mmol) and Bedford catalyst (0.003 g, 0.005 mmol) in a mixture of actonitrile/water (4/1, 3.1 mL) was heated under microwave irradiation for 30 min at 130° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was used without further purification. A solution of the protected amine in 6 M HCl (3 mL) was heated under microwave irradiation at 105° C. for 50 min. The solution was basified with Na2CO3 and extracted with ethyl acetate (3×10 mL). The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.384 g, 73%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[N:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[C:30]([C@@H:31]([F:42])[C:32]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=4)=[C:29]([CH:43]4[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]4)[C:28]4[C@@H:27]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=5)[CH2:26][C:25]([CH3:62])([CH3:61])[CH2:24][C:23]=4[N:22]=3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>O1CCCC1>[F:50][C:46]1([F:49])[CH2:47][CH2:48][CH:43]([C:29]2[C:28]3[C@@H:27]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)[CH2:26][C:25]([CH3:62])([CH3:61])[CH2:24][C:23]=3[N:22]=[C:21]([CH:18]3[CH2:17][CH2:16][N:15]([C:12]4[N:13]=[CH:14][C:9]([OH:8])=[CH:10][N:11]=4)[CH2:20][CH2:19]3)[C:30]=2[C@@H:31]([F:42])[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:36][CH:37]=2)[CH2:44][CH2:45]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O[Si](C)(C)C(C)(C)C)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(O)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 1.00 g (1.13 mmol) of (5S)-2-(1-{5-[(tert-Butyldimethylsilyl)oxy]pyrimidin-2-yl}piperidin-4-yl)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 13, in 2 ml of tetrahydrofuran, 1.5 ml of a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran was added, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, toluene and water were added to the reaction solution to separate an organic phase. Further, the reaction mixture was extracted with toluene from the aqueous phase. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=78/22-55/45 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 861 mg of the title compound as a white solid (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[F:15][C:16]([F:27])([F:26])[C:17]([O:19]C(=O)C(F)(F)F)=[O:18]>CC(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][CH:7]([C:17]([OH:19])([OH:18])[C:16]([F:27])([F:26])[F:15])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)CNC(=O)c1ccccc1Cl
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: O=C(NC(C(=O)O)C(O)(O)C(F)(F)F)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2 to 3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[C:31]([C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:38]=3)=[CH:35][CH:36]=2)=[CH:30][C:29]([CH2:47]O)=[N:28]1.C1C(=O)N([Br:56])C(=O)C1>C(Cl)Cl>[Br:56][CH2:47][C:29]1[CH:30]=[C:31]([C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:38]=3)=[CH:35][CH:36]=2)[N:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[N:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CO)nn3-c3ccccc3Cl)s2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CBr)nn3-c3ccccc3Cl)s2)c1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
PPh3 (4.36 g, 16.62 mmol) was added at 0° C. to a stirred solution of [1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]methanol (6.15 g, 13.85 mmol) in dry DCM. After 30 min, NBS (2.72 g, 15.28 mmol) was added portionwise at 0° C., and the mixture was stirred at it overnight. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (0-50% EtOAc/hexanes) to afford 3-bromomethyl-1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-thiophen-2-yl]-1H-pyrazole as a pale-yellow solid (3.6 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:12][S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].CC([O-])(C)C.[K+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[CH2:12][S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1cccc2ccccc12
Temperature: -20 °C

Procedure:
A stirred solution of 4-fluoro-nitrobenzene (1 equiv.) and chloromethyl-1-naphthylsulfone (1 equiv.) in dry THF under nitrogen at −78° C., was treated with 1.0 M KOt-Bu (2.2 equiv., 1.0 M in THF), warmed to −20° C. over 1 h period, quenched with acetic acid and treated sequentially with water, saturated aqueous NaHCO3 and extracted with ether. The combined extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was chromatographed (Silica gel, 1:1 and 1:0 ethyl acetate:hexanes as eluent) to give 1-(5-fluoro-2-nitrobenzyl-sulfonyl)naphthalene.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][NH:17]1>>[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][N:17]1[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3]
Reactant: c1ccc2c(c1)CNC2
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)N1Cc2ccccc2C1

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid 1.2 was reacted with isoindoline Ab following the procedure described in Example 1A. MS analysis (m−1)=331.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:10][C:9]([C:22](OCC)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[OH:23][CH2:22][C:9]1[CH:10]=[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(CO)nn1-c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of ethyl 1-phenyl-5-[(phenylsulfonyl)amino]-1H-pyrazole-3-carboxylate (445 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (4 mL) of diisobutylaluminum hydride in toluene was added dropwise. After stirring at 0° C. for 1 hr, the mixture was treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again, and the combined extracts were washed with 1.0 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:3) to give the title compound as a pale-yellow oil (yield 379 mg, yield 96%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.[Br:38][C:39]1[CH:44]=[N:43][C:42](I)=[CH:41][N:40]=1>CCOC(C)=O.O>[Br:38][C:39]1[N:40]=[CH:41][C:42]([C:14]2[C:15]([F:18])=[C:16]([F:17])[C:9]([N:4]3[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]3)=[C:10]([CH:13]=2)[CH:11]=[O:12])=[N:43][CH:44]=1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Reactant: Brc1cnc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CN(c2c(C=O)cc(-c3cnc(Br)cn3)c(F)c2F)CC(C)O1
Temperature: 55 °C
Yield: 64.5 %

Procedure:
To a suspension of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (Example 22, step 2) (1.5 g, 3.9 mmol) and sodium carbonate (1.1 g, 11 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added 2-bromo-5-iodo-pyrazine (1.0 g, 3.5 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.099 g, 0.14 mmol) was added at room temperature and the reaction was heated overnight at 55° C. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (5-40%) to obtain 931 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 3.02 (m, 2H), 3.40 (m, 2H), 4.19 (m, 2H), 8.28 (dd, J=8.2, 2.1 Hz, 1H), 8.74 (d, J=1.4 Hz, 1H), 8.78 (m, 1H), 10.29 (s, 1H) ; MS(APCl+) m/z 412, 414 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC)(OC)([O:20][CH3:21])[CH:17]([CH3:19])[CH3:18]>CCCCCC>[CH3:21][O:20][C:16](=[N:15][S:12]([C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)(=[O:14])=[O:13])[CH:17]([CH3:19])[CH3:18]
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Reactant: COC(OC)(OC)C(C)C
Solvent: CCCCCC
Product: COC(=NS(=O)(=O)c1nc(-c2ccccc2)ns1)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide and and 11 ml of trimethyl orthoisobutyrate was warmed to about 90° using an oil bath. After 2.5 hours, the solution was allowed to cool to room temperature, whereupon a precipitate formed. Hexane (25 ml) was added to complete the precipitation. The solid was collected, washed with hexane and vacuum dried (P2O5) to give 3.34 g of solid, m.p. 123°-124°.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OC)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=2[O:18][CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CNc2c([N+](=O)[O-])cc(Br)c3ccccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-bromo-1-methoxy-2-nitronaphthalene (3,5 g, 12.5 mmol) in dry tetrahydrofuran (15 ml) was dropwise added 2,4-dimethoxybenzylamine (8,5 g, 41,6 mmol) in dry tetrahydrofuran (15 ml). The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was submitted to flash chromatography (SiO2) eluting with toluene/ethyl acetate (1:1). The product was taken up in ethyl acetate and precipitated with light petroleum to give 4.1 g (78%) of the title compound. M.p. 104°-105° C.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:8][CH2:9]2)=[N:3]1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:32]=4[Cl:31])=[CH:17][CH:18]=3)=[O:20])[CH2:8][CH2:9]2)=[N:3]1
Reactant: Cn1cc2c(n1)-c1sccc1N(C(=O)c1ccc(N)cc1)CC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1cc2c(n1)-c1sccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice bath cooled mixture of 290 mg of 2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo[3,4-d]thieno[3,2-b]azepine in 4.0 ml of methylene chloride and 2.0 ml of dioxane under argon is added 186 μl of triethylamine followed by 156 μof 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 1N NaHCO3, 2N citric acid and brine. The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated in vacuo to give a foam residue which is crystallized from ethyl acetate to give 330 mg of the desired product as a white crystalline solid, m.p. 265°-267° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pt]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCC#Cc1cccc(Br)c1
Reactant: [H][H]
Agent: O=[Pt]
Product: OCCCCCc1cccc(Br)c1
Yield: 74 %

Procedure:
A mixture of an ethanolic solution of 5-(3-Bromo-phenyl)-pent-4-yn-1-ol (Example 3, step a) (1 g, 4.2 mmol)and platinum oxide (24 mg, 10% mol) was placed on a parr shaker for 4 hrs under 40 psi of hydrogen. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The resultant residu was purified by flash chromatography on silica gel, 1st 10:1 hexane/ ethyl acetate, 2nd 2:1 hexane/ethyl acetate as eluent, to give 5-(3-bromophenyl)pentan-1-ol as a clear oil, 0.75 g (74% yield); 1H NMR (DMSO-d6) δ 1.2 (m, 2H); 1.3 (m, 2H); 1.5 (m, 2 H); 3.3 (q, 2H); 4.3 (t, 1 H); 7.2 (m, 2 H); 7.4 (m, 2 H) MS [(+)ESI] m/z=243 [M−H]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
To a mixture of 4-bromo-3-fluoroaniline (13.3 g, 70.0 mmol), ethyl acrylate (9.48 mL, 87.5 mmol), tris(2-methylphenyl)phosphine (8.52 g, 28.0 mmol), N,N-diisopropylethylamine (50 mL) and N,N-dimethylformamide (50 mL) was added palladium(II) acetate (0.786 g, 3.50 mmol), and the mixture was stirred at 110° C. for 5 hr under an argon atmosphere. The reaction mixture was cooled, and the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was filtered off through celite. The filtrate was separated into the aqueous layer and the organic layer. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-60:40) to give the title compound (14.0 g, yield 96%). A part thereof was recrystallized to give yellow prisms.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:3]=1>C(N)CN.C(OCC)(=O)C>[ClH:1].[NH2:3][CH2:4][CH2:5][NH:6][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:3]=1
Reactant: CCn1cnc2c(Nc3cccc(F)c3)nc(Cl)nc21
Solvent: CCOC(C)=O
Solvent: NCCN
Product: CCn1cnc2c(Nc3cccc(F)c3)nc(NCCN)nc21
Product: Cl

Procedure:
0.2 g (0.62 mmol) of 2-chloro-9-ethyl-6-(3-fluoro-phenyl-amino)-9H-purine is stirred in 2.5 ml of ethylenediamine at 75° C. for 3 h, and the mixture is allowed to cool and is diluted with ethyl acetate. The organic phase is washed with water, separated off and dried over sodium sulfate. After removal of the solvent, the residue is dissolved in dioxane, and treated with 4 N HCl in dioxane. 2-(2-Amino-ethyl-amino)-9-ethyl-6-(3-fluor-phenyl-amino)-9H-purine hydrochloride is obtained as a crystalline precipitate by this procedure. This precipitate is filtered off and dried; m.p.>250° C.; FAB-MS: (M+H)+=315; Rf=0.6 (ethyl acetate:isopropanol:water:22% aqueous ammonium hydroxide solution=40:60:15:18).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([O-:9])=[O:8])=[CH:3][CH:2]=1.[Na+].O.Br[CH2:14][CH2:15][CH2:16][CH2:17][Sn:18]([CH3:21])([CH3:20])[CH3:19]>[Br-].C([P+](CCCC)(CCCC)CCCCCCCCCCCCCCCC)CCC.C1(C)C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([S:7]([CH2:14][CH2:15][CH2:16][CH2:17][Sn:18]([CH3:21])([CH3:20])[CH3:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C[Sn](C)(C)CCCCBr
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCCC[Sn](C)(C)C)cc1
Yield: 37.7 %

Procedure:
Into a 125 ml single-necked round bottom flask fitted with a teflon coated magnetic stir bar and a reflux condenser was charged 4.45 g of sodium p-toluenesulfinate, 20 ml water, 10 ml toluene, 7 g of 75% 4-bromobutyltrimethylstannane and 0.44 g of tri-n-butylhexadecylphophonium bromide. The mixture was refluxed for 2.5 hours with rapid stirring. On cooling, the organic phase was separated, dried over anhydrous magnesium sulfate and stripped of solvent on a rotary evaporator. The oil residue was distilled two times through a short path distillation head. The second distillation afforded 3.3 g of 4-(-p-tolylsulfonyl)butyltrimethylstannane, b.p. 136°-140° C. (1× 10-3 mm Hg). The presence of both the sulfonyl and trimethyltin moieties was indicated by strong infrared absorption bands at 1315 cm-1, 1300 cm-1, 1142 cm-1 (--SO2 --) and 765 cm-1 [(CH3)3Sn--]. NMR spectroscopy showed the following:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[N:19][CH:20]=[C:21]([F:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32]CCl>>[ClH:32].[F:23][C:21]1[CH:20]=[N:19][C:18]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:17]([CH:22]=1)[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)CC1
Reactant: ClCCl
Product: Cl
Product: O=C(NC1CCNCC1)c1cc(F)cnc1Oc1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
4-{[5-Fluoro-2-(4-fluorophenoxy)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (2.58 g, 5.95 mmol) (see Preparation 28) was dissolved in dichloromethane (15 ml) and hydrogen chloride gas bubbled through the solution at 0° C. for 10 minutes. The reaction mixture was then held under an atmosphere of nitrogen at room temperature for a further 45 minutes and the solvent tremoved in vacuo. The resultant white precipitate was triturated with diethylether (2-fold 10 ml) giving 5-fluoro-2-(4-fluoro-phenoxy)-N-piperidin-4-yl-nicotinamide hydrochloride (2.14 g) as a white solid.