Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:19][C:5]2[CH2:6][N:7]([C:10](=[O:18])[C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1.[Cl:32][CH2:33][C:34](=O)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].Cl.C(O)C>C(O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([N:7]2[CH2:8][CH2:9][C:4]3[C:3]4[C:2]([S:19][C:5]=3[CH2:6]2)=[N:1][C:34]([CH2:33][Cl:32])=[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:20]=4[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCN(C(=O)c2ccc(Cl)cc2)C3)cc1OC
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(CCl)nc2sc3c(c2c1-c1ccc(OC)c(OC)c1)CCN(C(=O)c1ccc(Cl)cc1)C3
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A mixture of 2-amino-6-(4-chlorobenzoyl)-3-(3,4-dimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (20.55 g), ethyl 4-chloroacetoacetate (8.17 g), hydrochloric acid-ethanol (23%, 7.34 g) and ethanol (80 ml) was stirred under refluxing conditions for 2.5 hours. The separating crystal was collected by filtration and recrystallized from ethyl acetate to yield ethyl 7-(4-chlorobenzoyl)-2-chloromethyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (for structural formula, see below) (12.38 g, 47%) as a light-yellow crystal having a melting point of 132 to 133° C. ##STR32##
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:15][CH:14]=3)[CH:12]=2)[CH:9]=1)[CH3:2].[F:31][B-](F)(F)F.F[B-](F)(F)F.F[N+]1C=CC=CC=1C1C=CC=C[N+]=1F.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH3:20])=[CH:15][CH:14]=3)[C:12]=2[F:31])[CH:9]=1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1
Agent: F[n+]1ccccc1-c1cccc[n+]1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOc1ccc2c(F)c(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
A mixture of tert-butyl {(1S)-2-[4-(6-ethoxypyrazolo[1,5-a]pyridin-2-yl)phenoxy]-1-methylethyl}carbamate (400 mg), 1,1′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (358 mg) and acetonitrile (3 mL) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as colorless crystals (129 mg).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C.O>[CH3:2][N:1]([C:21]([O:20][CH:16]([O:15][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])[CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: CNCC(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)C(OC(=O)c1ccccc1)OC(=O)N(C)CC(=O)O
Yield: 39.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.345 g, 3.8 mmols) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (1 g, 2.98 mmol) were reacted in an acetonitrile/water mixture (20 mL) to provide 0.364 g (39.5% yield) of the title compound (48) as a colorless, waxy material after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.05 (t, 2H), 7.59 (t, 1H), 7.43 (t, 2H), 6.84 (m, 1H), 4.21-3.88 (br m, 2H), 3.0 (d, 3H), 2.25 (m, 1H), 1.15 (dd, 6H). MS (ESI) m/z 332.20 (M+Na)+; 308.21 (M−H)−.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH3:7])[C:3](Br)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=1[OH:19].C(N(CC)CC)C>ClCCl>[Br:1][CH:2]([CH2:6][CH3:7])[C:3]([O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[O:9][CH3:8])=[O:4]
Reactant: COc1cc(C)cc(OC)c1O
Reactant: CCC(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Br)C(=O)Oc1c(OC)cc(C)cc1OC
Reaction time: 1.5 h

Procedure:
2-Bromobutyryl bromide (31.1 ml) was added to a stirred solution of 2,6-dimethoxy-4-methylphenol (45 g) in dry dichloromethane (500 ml), whereupon triethylamine (37.3 ml) was added dropwise over 30 minutes, maintaining the internal temperature below 10° C. using an ice-salt bath. During the addition a white precipitate formed. After addition was complete the reaction mixture was stirred for 1.5 hours, then filtered. The solid was washed with diethyl ether (200 ml) and the filtrate washed twice with saturated sodium bicarbonate solution (100 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the crude product as an oil (79.4 g). To remove any residual starting phenol, the oil was dissolved in diethyl ether and washed with sodium hydroxide solution (0.1 M; 3×100 ml), then water (4×100 ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed under reduced pressure to give the title compound as a yellow oil (72.9 g).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]C([O-])(C)C.[K+].CI>C1COCC1>[C:1]([N:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:16])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCNC(=O)OC(C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)CCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 80.8 %

Procedure:
To a solution of ethyl 3-aminopropionate hydrochloride (19 g) in THF (600 mL) was added triethylamine (44 mL), dimethylaminopyridine (1.5 g) and di-tert-butyldicarbonate (30 g) at 0° C. and the mixture was stirred at 40° C. for four hours. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl N-Boc-3-aminopropionate (16.7 g) as a colorless oil. To a solution of ethyl N-Boc-3-aminopropionate (5.0 g) in THF (50 mL) was added t-BuOK (2.8 g) and methyl iodide (4.9 g) at 0° C. and the mixture was stirred at room temperature for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 3-(N-Boc-N-methylamino)propionate (4.3 g) as a colorless oil. Subsequently, the title compound was prepared from ethyl 3-(N-Boc-N-methylamino)propionate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 1001.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1)#[N:2].C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC>C(OCC)(=O)CCC>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=Cc1ccccc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Solvent: CCCC(=O)OCC
Product: N#Cc1ccc(C=Cc2ccccc2)cc1
Yield: 26.8 %

Procedure:
The procedure described in Example 1 is followed, except that 16.55 g (0.1 mol) of 4-cyanobenzoyl chloride, 13.02 g (0.125 mol) of styrene, 35.37 g (0.1 mol) of tri-n-octylamine, 50 ml of ethyl butyrate as the solvent and 0.0575 g (0.0001 mol) of bis-(dibenzylideneacetone)-palladium(O) are used. After a reaction time of 2 hours at 100° C., 5.5 g (0.0268 mol) of 4-cyanostilbene, corresponding to a yield of 26.8% of theory, are obtained; melting point 119° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].I[CH2:30][CH3:31]>CN(C)C=O>[CH2:1]([N:3]([CH2:30][CH3:31])[CH2:4][CH:5]([N:7]1[C:20]2[CH:19]=[C:18]([C:21]#[N:22])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6])[CH3:2]
Reactant: CCI
Reactant: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 150 °C

Procedure:
A mixture of 10-(1-ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g), sodium carbonate (1.32 g) and iodoethane (1 cc) in dimethylformamide (50 cc) is heated to a temperature in the region of 150° C. for 6 hours. After cooling, the reaction mixture is concentrated to dryness (30 m Hg; 4 kPa) at 50° C. and the residue is taken up with ethyl acetate (100 cc) and washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-diethylamino-2-propyl)-2-phenothiazinecarbonitrile, D series (3.4 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:40][C:41]1[CH:46]=[CH:45][C:44]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])[CH3:39])[CH:15]([CH3:17])[CH3:16])=[O:19])[C@H:21]([C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)=[O:27])[CH2:22]2)=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc(F)cc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21

Procedure:
Intermediate 7 (486 mg, 0.89 mmol), 4-fluorophenylboronic acid (625 mg, 4.47 mmol), Cu(OAc)2 (406 mg, 2.24 mmol) and TEA (451 mg, 4.47 mmol) are all weighed into a flask, then dissolved in dry CH2Cl2 (20 mL). This mixture is stirred for 24 h. at room temperature, at which point some of the desired product had formed by LCMS. A further portion of boronic acid (625 mg, 4.47 mmol) is added and the mixture allowed to stir for a further 24 h, making the desired product the major peak, along with unreacted starting material. This reaction mixture is concentrated under reduced pressure, then loaded directly onto a plug of silica which is eluted with 10% Et2O/CH2Cl2 to isolate the desired product. Unreacted starting material remains at the column baseline under these conditions. The title compound is isolated as a off-white foam (188 mg, 33% yield): 1H NMR δ (CDCl3) 6.92-7.42 (m, 8H), 6.74 (v br s, 1H), 6.09 (br d, J=8.4 Hz, 1H), 3.97-5.27 (br m, 6H), 3.35-3.56 (br m, 2H), 2.62-3.16 (br m, 7H), 1.65-2.14 (m, 5H), 1.47 (s, 9H), 1.31 (br d, J=7.1 Hz, 2H), 1.14 (br d, J=7.1 Hz, 1H), 0.98 (brt, J=7.3 Hz, 2H), 0.79 (br d, J=6.7 Hz, 2H), 0.61 (br d, J=6.7 Hz, 2H); LCMS (APCl+) 639.4 (MH+, 100%).
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH2:7]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH3:10].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:7]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCN(CCCC)CCCCc1ccc(N)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Product: CCCCCCCN(CCCC)CCCCc1ccc(NS(C)(=O)=O)cc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A 250 ml 3-neck round bottom flask fitted with a thermometer, addition funnel, and calcium sulfate drying tube was charged with 8.5 g (0.027 mol) of N-butyl-N-heptyl-4-aminobenzenebutanamine and 90 ml of dry pyridine. The reaction mixture was cooled to a temperature of about 10°-15° C. and 2.6 ml (0.034 mol) of methanesulfonyl chloride was added thereto while maintaining the temperature below approximate 15° C. The external ice bath was removed and the reaction mixture was stirred overnight at room temperature. The volatiles were evaporated under reduced pressure and the pH of the reaction mixture was raised to about 9 by the addition of water and concentrated ammonium hydroxide. The aqueous solution was extracted four times with chloroform and the organic extracts were combined, washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated to provide 12.246 g of N-[4-[4-(butylheptylamino)butyl]phenyl]methanesulfonamide as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: Cn1c(CBr)nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cn1c(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1-methyl-1H-benzoimidazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (20%) as a colorless solid: mp>240° C.; 1H NMR (300 MHz, CDCl3) δ7.58-7.53 (m, 2H), 7.30-7.14 (m, 5H), 7.06-6.99 (m, 1H), 6.60 (s, 1H), 6.51 (s, 1H), 5.28 (ABq, 2H), 4.81 (d, J=9.3 Hz, 1H), 4.71 (d, J=9.3 Hz, 1H), 4.22-4.10 (m, 4H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.6, 154.5, 149.1, 144.1, 142.3, 141.7, 137.8, 136.1, 131.9, 128.5, 123.3, 123.0, 122.1, 121.5, 121.4, 118.6, 112.0, 110.1, 109.7, 98.5, 79.3, 64.1, 63.6, 57.3, 37.1, 29.8; MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:33]>CN(C)C=O>[CH2:25]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Cc1cn(C)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
NaH (180 mg of 60% oil dispersion, 4.5 mmol) is added to a solution of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (1.4 g, 3.6 mmol) in 20 ml dimethylformamide under N2 at 0° C. The resulting mixture is stirred for 20 minutes, then is allowed to warm to room temperature over 20 minutes. A 5 ml solution of iodomethane in dimethylformamide (7.2 mmol) is added dropwise and the reaction mixture is stirred for 1 hour. The reaction is quenched with cold aqueous NaHCO3, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.3 g of dibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (89%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:29])[CH3:28])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[OH:8][C@@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)[C:11](=[O:27])[C:10]1([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
To a solution of 4-((4S,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (232.2 mg) in THF (6 mL) was added tetrabutylammonium fluoride-THF solution (2.0 mL, 1 mol/L), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3), and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 38.9 mg, 22.9%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:15])[C:8](=[N:13]O)[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1.Cl.CCOCC>C(O)(=O)C.[Zn]>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:15])[CH:8]([NH2:13])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:3][CH:2]=1
Reactant: CCC(=O)C(=NO)C(=O)c1ccncc1
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCC(=O)C(N)C(O)c1ccncc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 20 ml acetic acid is dissolved 1.0 g of 1-(4-pyridyl)-1,3-diketo-2-oximinopentane with heat (50° C.). The solution is acidified with dry hydrogen chloride and 1.0 g of zinc dust is slowly added. The mixture is stirred for one hour and cooled. Dry ether is added to the mixture and the title compound precipitates from the solution as a crude solid. This may be used in subsequent steps without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:16]=[C:4]2[N:3]=1.O.[NH2:28][NH2:29]>O1CCOCC1.O>[CH3:15][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[CH:20]=[N:28][NH:29][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:16]=[C:4]2[N:3]=1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc4ncccc4c3)cc2n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc5ncccc5c4)cc3n2)c1
Reaction time: 8 h

Procedure:
There was suspended, in 1,4-dioxane (2.0 mL), 6-(5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-2-yl)-quinoline (83 mg, 0.23 mM) prepared in the preceding step 1, then hydrazine monohydrate (110 μL, 2.3 mM) was added to the suspension and the mixture was stirred for 8 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate thus obtained was diluted with water and then the mixture was extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting solid was dried in vacuo, suspended in ethanol (2.0 mL), then acetic acid (6.5 μL, 0.11 mM) and metatolualdehyde (30 μL, 0.25 mM) were added to the suspension and the mixture was stirred at room temperature for 2 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (60 mg, overall yield of these two steps: 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CCCc1ccc(B2OCC(C)(C)CO2)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
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: CCO
Solvent: O
Product: CCCc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (0.8 g, 2.4 mmol) was refluxed for 8 hours with dimethyl-2-(2-n-propylpyridin-5-yl)-1,3,2-dioxaborinane (0.72 g, 3.1 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol) and sodium carbonate (0.5 g) in tolune/ethanol/water 8:2:1 (11 ml). After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-n-propylpyridin-5-yl)phenyl]oxazoline was obtained, 0.20 g, pale solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1Br>CC(O)C>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[Br:19])[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccncc1Br
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2Br)CC1
Temperature: 100 °C

Procedure:
A mixture of benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 0.20 g, 0.81 mmol), 3,4-dibromo-pyridine (Chem. Abstracts, 58:5627) (0.19 g, 0.81 mmol) in IPA (0.5 mL) was heated at 100° C. in a sealed reaction tube for 7 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM IPA hexane)) to give 4-[(3-Bromo-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):405.27