Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([CH2:12][Br:13])[CH:9]=[CH:8][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: BrCc1ccnc(Br)c1
Temperature: 50 °C
Yield: 28.3 %

Procedure:
0.073 ml of acetic acid is added to a solution of 0.172 g of 2-bromo-4-methylpyridine in 2.5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20° C. The mixture brought, with stirring, to a temperature of 50° C. 0.356 g of N-bromosuccinimide and 0.048 g of benzoyl peroxide are added successively at this temperature. The mixture is maintained at 80° C. for about 18 hours. After cooling, the reaction medium is placed on a cartridge 20 mm in diameter packed with 10 g of 20-40 μm silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 5 ml/minute. The fractions between 30 and 40 ml are concentrated to dryness under reduced pressure. 0.071 g of 2-bromo-4-(bromomethyl)pyridine is thus obtained.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.C([O-])(=O)C.[Na+].[C:13]([C:15]1[CH:23]=[CH:22]C(C(N)=O)=[CH:17][CH:16]=1)#[N:14].[N+]([O-])([N+]([O-])=O)=O>C(O)(=O)C>[C:13]([C:15]1[CH:23]=[CH:22][C:6]([C:5]([OH:4])=[O:7])=[CH:17][CH:16]=1)#[N:14]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(C(N)=O)cc1
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 96 %

Procedure:
Acetic acid (30 ml), acetic anhydride (70 ml), sodium acetate (6.2 g), and p-cyanobenzamide (5.0 g) were mixed with stirring under cooling with ice, to thereby obtain a mixture. The mixture was allowed to react while dinitrogen tetroxide gas was introduced thereto at 381 N ml/minute for three hours. The residual solvent was removed through distillation in vacuum, and water was added to the residue, to thereby form crystals. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 4.83 g of p-cyanobenzoic acid (yield 96%, based on p-cyanobenzamide). The p-cyanobenzoic acid obtained had a purity of 97%.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1.[SH2:17]>N1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH2:16])=[S:17])[CH2:10][CH2:9]1
Reactant: S
Reactant: N#CCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)CN1CCOCC1
Reaction time: 8 h

Procedure:
A reaction mixture was prepared from 203 ml. each of triethylamine and pyridine plus 63 g. of morpholinoacetonitrile. Hydrogen sulfide was bubbled through the heated, stirred reaction mixture for about 2.5 hours. Stirring was continued overnight at ambient temperature. The next day, H2S was passed through the heated, stirred reaction mixture for an additional 1.5 hours. At this point, the solvents were evaporated in vacuo and the residue triturated with ether. The ether was discarded and the residue dissolved in ethanol. Crystalline morpholinothioacetamide formed in the above reaction precipitated and was separated by filtration. Treatment of the filtrate with alcoholic hydrogen chloride yielded morpholinothioacetamide hydrochloride melting in the range 64°-80° C. See also J.A.C.S., 72, 2804 (1950).
Reaction SMILES: CCN(CC)CC.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.Cl[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].CC([O-])(C)C.[K+]>C1COCC1.O>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]2[CH2:19][CH2:20][CH2:21][C:22]2=[O:23])=[C:12]([CH3:17])[CH:11]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCCC2=O)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of Et3N (156 mL, 1 eq) and 4-methoxy-2-methylaniline (150 g, 1.09 mole) in anh. THF (2.4 L), in a 10 L reaction vessel, at 0° C., under N2, was added dropwise a solution of 4-chlorobutyryl chloride (126 mL, 1 eq) in anh. THF (480 mL). The internal temperature was maintained at circa 10° C. and the reaction mixture was stirred for 1.5 hr. It was cooled down to 0° C. and KOt-Bu 1M/THF (2.64 L, 2.4 eq) was added dropwise over a period of 1.5 hr, keeping the internal temperature <10° C. The reaction mixture was stirred at that temperature for 30 min. Water (1.5 L) was then added slowly (20 min) and the phases were separated. The organic layer was treated with conc. HCl (250 mL) and water (1.26 L) and the phases were separated. The combined aqueous layers were extracted with EtOAc (2.6 L) and the combined organic layers were washed with brine (2 L). The solvent was evaporated and the residue purified by flash chromatography (Biotage 150, EtOAc/cHex 8:2) to give the title compound as a pale brown solid (206 g, 92%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:40][OH:41])[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19]2[C:28]([CH3:29])=[N:27][C:26]3[C:21](=[C:22]([C:30]4[NH:34][C:33]5[C@@H:35]([CH3:39])[NH:36][C:37](=[O:38])[C:32]=5[CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13]1)=[O:10])(C)(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[NH2:7][C@H:8]([CH2:40][OH:41])[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][C:19]2[C:28]([CH3:29])=[N:27][C:26]3[C:21](=[C:22]([C:30]4[NH:34][C:33]5[C@@H:35]([CH3:39])[NH:36][C:37](=[O:38])[C:32]=5[CH:31]=4)[CH:23]=[CH:24][CH:25]=3)[N:20]=2)[CH2:13]1)=[O:10]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](NC(=O)[C@@H](CO)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](NC(=O)[C@H](N)CO)C1
Yield: 96.6 %

Procedure:
A solution of tert-butyl((R)-3-hydroxy-1-(((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)amino)-1-oxopropan-2-yl)carbamate (491, 34 mg, 0.059 mmol) and TFA (0.45 mL, 5.89 mmol) in DCM (0.29 mL) was stirred at 0° C. to RT for 15 min. It was concentrated under reduced pressure. The crude product was dissolved in methanol and injected (3×1 mL) onto the Shimadzu preparative LC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 100% over 12 min) before the pure fractions were combined and concentrated via rotary evaporation to give (R)-2-amino-3-hydroxy-N-((1R,3S)-3-((3-methyl-8-((R)-6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinoxalin-2-yl)amino)cyclohexyl)propanamide 2,2,2-trifluoroacetate (497, 34 mg, 0.057 mmol, 98% yield) as a red oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.28 (m, 1H) 1.29-1.39 (m, 1H) 1.43-1.52 (m, 2H) 1.45 (d, J=6.65 Hz, 3H) 1.86 (d, J=10.56 Hz, 2H) 2.06-2.15 (m, 2H) 2.53 (s, 3H) 3.55-3.64 (m, 1H) 3.65-3.80 (m, 3H) 4.13-4.26 (m, 1H) 4.55 (q, J=6.85 Hz, 1H) 6.90 (d, J=8.02 Hz, 1H) 6.96 (d, J=1.37 Hz, 1H) 7.33 (t, J=7.73 Hz, 1H) 7.57-7.64 (m, 2H) 7.84 (d, J=7.43 Hz, 1H) 8.00-8.10 (m, 3H) 8.36 (d, J=7.82 Hz, 1H) 11.94 (s, 1H). MS (ESI, pos. ion) m/z: 478.1 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH:13]4[O:16][CH:14]4[CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])(=[O:3])[CH3:2].[Br-].[Mg+2].[Br-]>C1(C)C=CC=CC=1.O>[C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[CH2:13][C:14](=[O:16])[CH2:15][CH:6]([C:7]=23)[CH:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cccc3c2C(CC2OC32)C1c1ccccc1F
Agent: [Br-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1c2cccc3c2C(CC(=O)C3)C1c1ccccc1F
Yield: 103.8 %

Procedure:
A portion (0.53 g) of the compound obtained in Example 250 was dissolved in anhydrous toluene (100 ml) and to the solution was added magnesium bromide etherate (5.54 g). The mixture was heated to reflux for 4 hours and allowed to cool. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to yield 0.55 g of the titled compound as a crude yellow solid. The compound was used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[C:11]3[N:12]=[C:13]([CH3:28])[C:14]([C@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])=[C:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:34]([CH3:37])([CH3:36])[CH3:35])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl.CCOCC>[C:34]([O:27][C@@H:22]([C:14]1[C:13]([CH3:28])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:29]=2)[C:15]=1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:23]([O:25][CH3:26])=[O:24])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.067 g, 0.162 mmol) and tert-butyl acetate (1 ml, 7.40 mmol) in CH2Cl2 (3 mL) was added 70% perchloric acid (0.042 ml, 0.486 mmol) at rt. After 2 h, the reaction was diluted with Et2O (50 mL), washed with sat. Na2CO3 (2×5 mL), dried (Na2SO4), filtered and concentrated to give yellow solid which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0481 g, 0.102 mmol, 63.2% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.96 (t, J=1.5 Hz, 1H), 7.87 (dt, J=7.6, 1.3 Hz, 1H), 7.41-7.31 (m, 2H), 6.75 (s, 1H), 5.40 (s, 1H), 3.87-3.77 (m, 1H), 3.70 (s, 3H), 2.93-2.79 (m, 2H), 2.73 (s, 3H), 1.96-1.85 (m, 2H), 1.77-1.68 (m, 2H), 1.54-1.38 (m, 4H), 1.25 (s, 9H). LCMS (M+H) calcd for C26H33ClN3O3: 470.22. found: 472.4.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])([CH3:38])[CH3:37]>C(Cl)Cl>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:8][C:7]1[CH:15]=[CH:16][C:4]([C:1]2[O:3][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH:36]([CH3:37])[CH3:38])=[C:50]([OH:51])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:14]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl (4-acetyl-phenoxy)acetate (2.14g, 9.67 mmol), trimethylsilyl triflate (4.48 mL, 23.20 mmol), triethylamine (12.93 mL, 38.6 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (2.00g, 6.45 mmol) m.p. 194°-196° C.; ; 1H NMR (400 MHz, DMSO-d6) δ 1.57 (m, 9H), 3.41 (m, 1H), 4.81 (q, 2H), 4.89 (s, 2H), 6.75 (s, 1H), 6.90 (d, 1H), 7.05 (m, 4H), 7.26 (d, 1H), 7.79 (d, 2H).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([CH:9]1[CH2:13][C:12](=O)[CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:9]1[CH2:13][C:12](=[CH2:1])[CH2:11][CH:10]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8]
Reactant: CCOC(=O)C1CC(=O)CC1CC
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CC(CC)C(C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of KOt-Bu (3.65 g, 32.6 mmol) and methyltriphenylphosphonium bromide (11.6 g, 32.6 mmol) in THF (69.5 mL) was cooled to about −10° C. A solution of ethyl 2-ethyl-4-oxocyclopentanecarboxylate (4.00 g, 21.7 mmol) in THF (17.4 mL) was added dropwise while the temperature was kept at about 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for about 16 h. The insoluble material was removed by filtration. The filtrate was concd under reduced pressure. The resulting material was purified by silica gel (120 g) chromatography eluting with a gradient of 0-20% EtOAc in heptane to provide ethyl 2-ethyl-4-methylenecyclopentanecarboxylate (2.55 g, 64%) as a colorless liquid: 1H NMR (d-DMSO) δ 4.88-4.78 (m, 2H), 4.16-3.96 (m, 2H), 2.66-2.31 (m, 4H), 2.24-1.82 (m, 2H), 1.50 (m, 1H), 1.35-1.22 (m, 1H), 1.18 (t, 3H), 0.85 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:15]=2)[CH2:10][C@@H:9]1[C:32]([OH:34])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:36][NH:37][CH3:38].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C>CN(C=O)C.O>[CH3:36][N:37]([CH3:38])[C:32]([C@H:9]1[CH2:10][C@H:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[N:15]=2)[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:34]
Reactant: CNC
Reactant: COc1ccccc1-c1nc(N[C@H]2C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(N[C@H]2C[C@H](C(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Yield: 89.7 %

Procedure:
A solution of (2R,4S)-1-(tert-butoxycarbonyl)-4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-2-carboxylic acid (0.095 g, 0.204 mmol), dimethylamine hydrochloride (0.017 g, 0.204 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.077 g, 0.204 mmol), and triethylamine (0.037 mL, 0.265 mmol) in DMF (1 mL) was stirred for 24 hours. Water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). The organic extracts were combined, dried (MgSO4) and concentrated. Purification by silica gel chromatography (10% methanol in dichloromethane) gave the title compound as a solid (0.090 g, 90%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[C:15]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:22][C:16]1[C:15]([F:23])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]#[N:21].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N2CCNCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.72 g) in dichloromethane (5 mL) was added trifluoroacetic acid and the reaction mixture was stirred at room temperature for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (0.63 g). MS (m/e): 224.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:16])[C:5]2[C:6](=O)[N:7]3[CH2:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.Cl>C(O)(=O)C.C(O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:16])[C:5]2[CH2:6][N:7]3[CH2:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=c1c2c(Cl)cc(Cl)cc2nc2n1CCC2
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1cc(Cl)c2c(c1)N=C1CCCN1C2
Reaction time: 0.17 h

Procedure:
To a mechanically stirred solution of 1.5 g of the above 6,8-dichloro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one in 150 mL of glacial acetic acid at 60° C. was added 25 g of zinc dust. To this suspension was then added dropwise a solution of 35 mL of concentrated hydrochloric acid in 50 mL of glacial acetic acid in 20 minutes. After the addition was complete, the mixture was stirred for an additional 10 minutes. Then the unreacted zinc was filtered off (Caution!, Pyrophoric!), washed with 4×30 mL of glacial acetic acid and the filtrate was concentrated in vacuo. To the residue was added 80 mL of 20% aqueous sodium hydroxide and the product was extracted with tetrahydrofuran (3 times 150 mL). The organic extract was concentrated in vacuo and the residue was distributed between 100 mL of chloroform and 25 mL of water. The aqueous layer was extracted with 2×25 mL of chloroform. The combined extract was dried with anhydrous potassium carbonate, filtered, concentrated in vacuo, and flash chromatographed on silica gel, using 10:1 chloroform-methanol as eluent. The base was treated with 1 equivalent of 4N HCl in 50 mL absolute ethanol, concentrated in vacuo, redissolved in 50 mL absolute EtOH, concentrated, repeated again. Then the white solid was recrystallized from absolute EtOH-EtOAc, giving after drying in vacuo 0.8 g of 6,8-dichloro-1,2,3,9-tetrahydropyrrolo[2,1-b]-quinazoline hydrochloride in the form of white crystals, m.p. 305° C.-310° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CO
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 96 h

Procedure:
Approximately 85 mL of methanol was placed in a 1 liter glass bottle with a screw cap. The solution was saturated by dissolving approximately 10.5 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, and the resulting solution was stirred. Once the solution was saturated, an additional 17 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the saturated solution to create a suspension. The cap was sealed and the saturated suspension was allowed to stir and equilibrate for about four days.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=S(=O)(NCc1ccccc1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 57.9 %

Procedure:
4-Bromobenzenesulfonyl chloride (14.05 g, 55 mmol) was added to a stirred solution of benzylamine (5.36 g, 50 mmol) and pyridine (400 ml) under nitrogen at room temperature. The resulting reaction mixture was stirred for 1 hr; then it was poured onto ice/water (800 ml) to form a yellow precipitate which was filtered and recrystallized from EtOH/water to give 9.44 g (53%) of the title compound as off-white needles, mp 116°-117° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1[C:39]([CH:40]=O)=[CH:38][C:37]2[O:42][C:43]([F:46])([F:45])[O:44][C:36]=2[CH:35]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:46][C:43]1([F:45])[O:44][C:36]2[CH:35]=[CH:34][C:39]([CH2:40][N:29]3[CH2:28][CH2:27][CH:26]([N:23]4[C:19]5=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]6[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=6)=[C:18]5[CH:25]=[N:24]4)[CH2:31][CH2:30]3)=[CH:38][C:37]=2[O:42]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccc4c(c3)OC(F)(F)O4)CC2)cc1

Procedure:
1-[1-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidin-4-yl]-4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 2,2-difluoro-5-formylbenzodioxole (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.98 (m, 2H), 2.15-2.25 (m, 4H), 2.92-2.98 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.57 (s, 2H), 4.77-4.83 (m, 1H), 7.18-7.20 (m, 1H), 7.35-7.39 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=544.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[NH2:1][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:14]([CH3:23])[C:13]2=[CH:24][CH:25]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1c2ccc(OCCCBr)cc2C1CN1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1c2ccc(OCCCN)cc2C1CN1CCCCC1

Procedure:
Sodium azide (1.49 g) is added to a stirred solution of 5-(3-bromopropoxy)-2-methyl-1-(1-piperidinylmethyl)benzocyclobutene (7.3 g) dissolved in a mixture of ethanol/water (7.3 ml/73 ml). The reaction mixture is refluxed overnight, poured into water and extracted with ether. The organic extract is washed with sat'd aqueous NaCl, dried, filtered and evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@H:6]([N:13]1[CH:17]=[C:16]([N+:18]([O-])=O)[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[CH2:30][CH:29]([NH:35][C@@H:36]([CH2:40][CH2:41][CH3:42])[C:37](O)=[O:38])[CH2:28][CH2:27]2>>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][NH:4][CH2:5][C@@H:6]([N:13]1[CH:17]=[C:16]([NH:18][C:37](=[O:38])[C@@H:36]([NH:35][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:40][CH2:41][CH3:42])[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(C)(C)CNC[C@@H](c1ccccc1)n1cnc([N+](=O)[O-])c1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn([C@H](CNCC(C)(C)C)c2ccccc2)cn1

Procedure:
(R)-2,2-dimethyl-N-(2-(4-nitro-1H-imidazol-1-yl)-2-phenylethyl)propan-1-amine was reduced and coupled with (S)-2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 538 m/z (M+1).