Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[F:30][B-](F)(F)F.C(N([S+](F)F)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([F:30])[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cn2)COC1
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC1(c2ccc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of the product of Step 1, Example 8 (300.0 mg, 1.30 mmol) in methylene chloride (3.00 mL) is added to a mixture of triethylamine trishydrofluoride (0.531 mL, 3.26 mmol), triethylamine (0.273 mL, 1.96 mmol), and (Diethylamino)difluorosulfonium tetrafluoroborate (597 mg, 2.61 mmol) in methylene chloride (20.0 mL) at −78° C. The reaction mixture is slowly allowed to warm to 0° C. More (Diethylamino)difluorosulfonium tetrafluoroborate (100.0 mg, 0.437 mmol) is added and stirring continued at this temperature for 1 hour. The mixture is diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution, brine, dried over magnesium sulfate, and then concentrated. The residue is purified by chromatography on silica gel eluting with a gradient of 0-30% ethyl acetate to afford the title compound (200 mg): MS (ESI+) m/z 232.1/234.1 [M+H].
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[C:29]1([CH:35]([NH2:37])[CH3:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:37][CH:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:36])=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(N)c1ccccc1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC(C)c3ccccc3)n(C)c2n1

Procedure:
4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-phenylethanamine via General Procedure E to give 10.8 mg of 279 following reverse phase purification. MS (Q1) 483.2 (M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[N+]=[N-])[CH3:11]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH2:10]([O:12][C:13]([C@@H:14]1[CH2:6][C@H:5]1[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:17])[CH3:11]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cccc(F)c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A round-bottomed flask was charged with 3-fluorostyrene (13.0 g, 0.107 mol) in anhydrous methylene chloride (130 mL). To this mixture was added rhodium acetate dimer (1.30 g, cat amount). A solution of ethyldiazoacetate (33.28 g, 0.291 mol) in anhydrous methylene chloride (130 mL) was added to the reaction via a syringe pump over 5 h and stirred at room temperature for 1 h in darkness. The reaction mixture was filtered through a plug of celite, which was washed with water followed by brine. The organic layer Was dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc/petroleum ether 1:9) gave rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid ethyl ester (13.0 g, 59%) as a colorless liquid sufficiently pure for the next step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH3:9])[C:5]([CH3:8])([OH:7])[CH3:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:7][C:5]([CH3:8])([C:4]([F:10])([F:3])[CH3:9])[CH3:6]
Reactant: CC(C)(O)C(C)(F)F
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(F)(F)C(C)(C)OC(=O)Oc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.652 g, 16.31 mmol) in THF (25 mL) was added 3,3-difluoro-2-methylbutan-2-ol (1.84 g, 14.82 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (3.20 g, 14.82 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 10-50% EtOAc in hexanes to afford the desired product 3,3-difluoro-2-methylbutan-2-yl pyridin-2-yl carbonate (500 mg, 13.76%) as an oil that later crystallized to a white solid upon standing. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.43 (ddd, J=4.9, 2.0, 0.7 Hz, 1H), 7.95-7.75 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (dt, J=8.2, 0.8 Hz, 1H), 1.72 (s, 6H), 1.77-1.66 (m, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:11][Si:10]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
4-iodophenytrimethyl silylacetylene (5.0 g, 16.6 mmol), 4-n-butylphenylacetylene (2.67 g, 16.0 mmol), CuI (32 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.35 g, 0.48 mmol), triethylamine (50 mL) and THF (50 mL) were added together and stirred at ambient temperature under N2 for 18 h. The reaction mixture was filtered to remove solids and concentrated to dryness, redissolved in CHCl3, washed with water (2×), brine, dried with MgSO4, filtered, concentrated and the solid recrystallized from hexanes to give 2.10 g (40%) product. The crude product could also be purified by washing with MeOH. This gave 1.94 g additional product for a total yield of 79%. 1H NMR (CDCl3) δ: 7.46 (m, 6H), 7.20 (d, J=8.1 Hz, 2H); 2.63 (t, J=7.6 Hz, 2H); 1.62 (m, 2H); 1.38 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); 0.28 (s, 9H). 13C{1H} NMR (CDCl3): 143.7, 131.9, 131.6, 131.3, 128.5, 123.6, 122.7, 120.1, 104.7, 96.1, 91.6, 88.4, 35.6, 33.4, 22.3, 14.0, −0.1 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[CH:14][C:15]4[C:16](=[O:33])[NH:17][C:18]([C:22]5[CH:27]=[CH:26][C:25](Br)=[CH:24][C:23]=5[O:29][CH2:30][CH2:31][CH3:32])=[N:19][C:20]=4[CH:21]=[C:12]3[N:11]=[CH:10]2)=[CH:4][CH:3]=1.[Cu][C:35]#[N:36].N>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[CH:14][C:15]4[C:16](=[O:33])[NH:17][C:18]([C:22]5[CH:27]=[CH:26][C:25]([C:35]#[N:36])=[CH:24][C:23]=5[O:29][CH2:30][CH2:31][CH3:32])=[N:19][C:20]=4[CH:21]=[C:12]3[N:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCCOc1cc(Br)ccc1-c1nc2cc3ncn(Cc4ccc(F)cc4)c3cc2c(=O)[nH]1
Agent: N
Solvent: CN1CCCC1=O
Product: CCCOc1cc(C#N)ccc1-c1nc2cc3ncn(Cc4ccc(F)cc4)c3cc2c(=O)[nH]1
Temperature: 25 °C
Yield: 91 %

Procedure:
1-(4-Fluorophenylmethyl)-6-(4-bromo-2-propoxyphenyl)-1H-imidazo[4,5-g]quinazolin-8(7H)-one (507 mg, 1 mmol) was dissolved in 6 mL N-methyl-2-pyrrolidinone containing copper (I) cyanide (178 mg, 2 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and poured into 100 mL of 2N aqueous ammonia solution. The solid that precipitated was collected by filtration and washed first with 2N aqueous ammonia, then water and dried in a vacuum oven at 45° C. overnight to afford the title compound as a yellow solid (464 mg, 0.91 mmol, 91% yield). HPLC: (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.65 minutes.
Reaction SMILES: [O-][CH2:2]C.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15](=[O:21])[NH:16][C:17](=[S:20])[NH:18][CH:19]=2)=[CH:9][N:8]=1.CI>CCO>[CH3:5][O:6][C:7]1[N:8]=[CH:9][C:10]([CH2:13][C:14]2[C:15](=[O:21])[N:16]=[C:17]([S:20][CH3:2])[NH:18][CH:19]=2)=[CH:11][N:12]=1
Reactant: CC[O-]
Reactant: COc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
Into a stirred solution of sodium ethoxide (1.358 mmol, 2 eq) in EtOH (3 ml) was added 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.679 mmol, 1 eq) at rt. After 30 min, the reaction mixture was treated with methyl iodide (1.358 mmol, 2 eq) and was stirred at rt overnight. Solvent was evaporated and a crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of EtOAc in Cyclohexane: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.568 mmol, yield=83%, purity=46%). [M+H]+=265.25 1H NMR (300 MHz, DMSO-d6) δ/ppm 2.39 (s, 1H), 3.82-3.87 (m, 3H), 7.75 (s, 1H), 8.47 (s, 2H)
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>>[CH2:1]([NH:6][C:7]([NH:9][C:10]1[N:15]=[N:14][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use pentylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (45.5% yield). 1H NMR (400 MHz, CDCl3) δ 10.60, 7.82, 7.74, 7.13, 7.63, 7.56, 7.52, 7.36, 7.08, 4.29, 4.0-4.09, 3.85-3.95, 3.50-3.70, 3.40-3.47, 3.25-3.36, 1.50-1.60, 1.22-1.36, 0.80-0.92. MS (ES+) m/z 465 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:20])([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.Cl[CH2:22][CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[O:26]>>[CH3:36][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:25]([CH2:24][CH2:23][CH2:22][N:17]2[CH2:16][CH2:15][CH:14]([C:7]([OH:20])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)=[O:26])=[CH:28][CH:29]=1)([CH3:34])[CH3:35]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
reacting azacyclonol with 4 -chloro-1-[4-(1,1-dimethylethyl)phenyl]-1-butanone to yield terfenadone free-base;
Reaction SMILES: C(C(CC1C=CC(OC)=CC=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:33])[C:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])=[N+:18]=[N-:19])[CH:13]([CH:34]([O:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[O:38])[CH3:35])[C:12]1=[O:50])C1C=CC(OC)=CC=1.O>C(#N)C.O>[N+:47]([C:44]1[CH:43]=[CH:42][C:41]([CH2:40][O:39][C:37]([O:36][CH:34]([CH:13]2[CH:14]([CH2:15][C:16](=[O:33])[C:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=3)=[O:21])=[N+:18]=[N-:19])[NH:11][C:12]2=[O:50])[CH3:35])=[O:38])=[CH:46][CH:45]=1)([O-:49])=[O:48]
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)C(=[N+]=[N-])C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)NC1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
1.27 g 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone was dissolved in 50 ml of acetonitrile-water (9:1 by volume), and 2.7 g of ceric ammonium nitrate was added thereto all at once under ice-cooling. After vigorously stirring, the mixture was further stirred at room temperature for 30 minutes. Cool water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel chromatography to obtain 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C@H:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C=C(N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H](N[C@@H](C)c1ccc(OC)cc1)c1cccnc1
Reaction time: 30 h

Procedure:
The crude methyl N-[(S)-1-(4-methoxyphenyl)ethyl]-3-amino-3-(3-pyridyl)propenoate, (40.6 g, 130 mmol) was dissolved in methanol (200 mL) and mixed with 20% Pd(OH)2/C (4.1 g). The mixture was hydrogenated under atmospheric pressure for 30 h. The mixture was diluted with ethyl acetate (50 mL) and filtered through celite (20 g) to remove the catalyst. The celite was washed with hot (70° C.) ethyl acetate (200 mL). The combined filtrate was concentrated under reduced pressure to near dryness to an oily residue. Crude amine (27.5 g) was dissolved in hot ethyl acetate (40 mL). The resulting hot yellow solution was filtered and rinsed with 15 mL of hot ethyl acetate. The clear solution was concentrated to <50 mL and allowed to stand at room temperature overnight. The resulting white crystalline solid was collected by filtration and washed with cold ethyl acetate (EtOAc) (˜15-20 mL), then air dried. Yield of isolated solid: 15.5 g. HPLC analysis showed >99% desired diastereomer. A second crop was obtained from the filtrate after concentration to about 20 mL. Yield: 1.7 identical by HPLC to first crop; total yield: 17.2 g (62.5%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[CH:25]([C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=2[S:30][CH:31]=1)=O.CCCCC>ClCCl.[Zn]>[Br:20][C:21]([Br:24])=[CH:25][C:27]1[C:28]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:29]=2[S:30][CH:31]=1
Reactant: Cc1cccc2c(C=O)csc12
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: Cc1cccc2c(C=C(Br)Br)csc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.04 g of Zn dust and 4.17 g of triphenylphosphine are taken up in dichloromethane and 5.27 of tetrabromomethane dissolved in dichloromethane added dropwise under inert gas and with cooling. Following stirring for 24 hours at room temperature 1.4 g of 3-formyl-7-methylbenzo[b]thiophene dissolved in dichloromethane are added dropwise with ice-cooling and stirring continued overnight at room temperature. Pentane is added and the precipitated Ph3PO filtered off. Evaporation of the filtrate under vacuum yields a residue which is chromatographed over silica gel to yield the title compound, M.p.=75°-78°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][C:18]1[CH:17]=[C:16]([C:13]2[N:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:24]=[C:2]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:3]=[CH:4][C:5]=3[N+:25]([O-:27])=[O:26])=[N:11][CH:12]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])cn2)cc1C
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])cn2)cc1C
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitrobenzamide (3.66 g, 9.56 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL), piperidine (3.8 g, 44.71 mmol, 4.70 equiv), and potassium carbonate (3.96 g, 28.70 mmol, 3.00 equiv). The resulting solution was stirred for about 8 h at 85° C. in an oil bath. The reaction was then quenched with 450 mL of water. The resulting solution was extracted with 3×300 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 3.86 g (crude) of N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitro-5-(piperidin-1-yl)benzamide as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH:32]#[C:33][CH:34]([OH:37])[CH2:35][CH3:36]>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:32]#[C:33][CH:34]([OH:37])[CH2:35][CH3:36])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: C#CC(O)CC
Product: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Example 69) was coupled to 1-pentyn-3-ol (Aldrich, St. Louis, Mo.) to afford 1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol as a mixture of enantiomers.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([NH2:10])[CH2:6][CH2:7][CH2:8][NH2:9]>>[NH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:10][CH2:3][CH2:2][C:1]#[N:4]
Reactant: NCCCCN
Reactant: C=CC#N
Product: N#CCCNCCCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Acrylonitrile (5.08 g, 0.096 mol) was added to ice bath-cooled 1,4-butanediamine (8.44 g, 0.096 mol) in 30 min. The resulting mixture was stirred for 2 h at RT, heated to 50° C. for further 3 h and finally let stirring at RT overnight. After Kugelrohr distillation colourless oil was obtained (5.80 g, 0.041 mol, yield 42.8%).
Reaction SMILES: C(N(CC)CC)C.[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>ClCCl>[I:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](=[O:14])[NH:23][CH2:22][C:21]([O:20][CH3:19])=[O:24])=[CH:11][CH:10]=1
Reactant: COC(=O)CN
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1ccc(I)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Triethylamine (5.4 ml) was added to a solution of 4-iodobenzoyl chloride (5.06 g) in dichloromethane (30 ml) at 5° C. Glycine methyl ester hydrochloride (2.4 g) was then added to the reaction mixture and the mixture was stirred at 5° C. for 2 hours. The mixture was then stirred at ambient temperature overnight. Dichloromethane (100 ml) was added and the mixture was washed with water (2×100 ml), dried (MgSO4) and evaported. The residue was triturated with pentane to give a solid which was collected by filtration to give methyl 4-iodohippurate, m.p. 166-168° C. NMR: 3.65(3H,s), 4.0(2H,d), 7.65(2H,m), 7.88(2H,m) and 9.0(1H,m); m/z 320(M+H).
Reaction SMILES: [OH-].C[N+](C)(C)C.[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[OH:9][CH2:8][C:7](=[O:11])[O:10][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(C)Br
Reactant: O=C(O)CO
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)OC(=O)CO
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Tetramethylammonium hydroxide (25% in methanol) was added to a stirring solution of glycolic acid (3.8 g, 50 mmol) in 5 mL dimethylformamide cooled on ice until a pH of 7 was indicated by moistened pH paper. Methyl 2-bromopropionate (6.1 mL, 55 mmol) was added and the reaction was stirred at room temperature for 5 d. The reaction mixture was filtered, the solids were washed with ethyl ether, and the combined filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b.p. 64° C./0.05 mm Hg; 1H NMR δ 1.53 (d, 3H, J=7.2 Hz), δ 2.78 (bs, 1H), δ 3.77 (s, 3H),δ 4.24 (d, 1H, J=17.4 Hz) δ 4.31 (d, 1H, J=17.4 Hz), δ 5.22 (q, 1H, J=7.1 Hz), HRMS calcd for C6H9O5Tms (M--CH3) 219.0688, obsd 219.0708.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[C:21]([CH:22]4[CH2:27][O:26][CH2:25][CH2:24][O:23]4)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=3[N:17]=2)=[O:11])[CH2:3][CH2:2]1>CO.ClCCl.[Pd]>[O:23]1[CH2:24][CH2:25][O:26][CH2:27][CH:22]1[C:21]1[C:15]2[S:14][C:13]([NH:12][C:10](=[O:11])[C:9]3[CH:30]=[CH:31][N:32]=[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:8]=3)=[N:17][C:16]=2[C:18]([O:28][CH3:29])=[CH:19][CH:20]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C4=CCOCC4)c3)nc12
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a stirred solution of 130 mg (0.29 mmol) (±)-2-(3,6-dihydro-2H-pyran-4-yl)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide in 10 ml methanol and 10 ml dichloromethane was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. Flash chromatography (2/49/49 methanol/dichloromethane/ethyl acetate) followed by trituration in ether afforded 60 mg (46%) (±)-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 456 (M+H+, 100).