Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([CH2:13][C:14]#[N:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][NH2:17]>C(O)C>[C:1]1([C:11]2[CH:13]=[C:14]([NH2:15])[NH:17][N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: N#CCC(=O)c1cccc2ccccc12
Solvent: CCO
Product: Nc1cc(-c2cccc3ccccc23)n[nH]1
Temperature: 25 °C

Procedure:
1-Naphthoylacetonitrile (161 mg, 0.825 mmol) and hydrazine (0.11 mL, 3.5 mmol) are heated in ethanol (1.1 mL) at 70° C. in a sealed vial for 60 hr. The reaction is cooled to room temperature and the solvent is removed. The crude material is taken up in 5 ml of ethyl acetate and washed with water and brine. The organic layer is concentrated in vacuo to give 3-(1-naphthyl)-1H-pyrazol-5-amine which is dissolved in acetic acid (0.375 mL, 6.60 mmol). Diethyl ethoxymethylenemalonate (0.182 mL, 0.907 mmol) is added and the mixture is heated at 120° C. for 3 hr in a sealed vial. During the reaction, a precipitate forms. The reaction is cooled to room temperature and the solid is collected in a Buchner funnel and washed with reagent grade alcohol to provide ethyl 2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (166 mg, yield 60%). 1H NMR (300 MHz, DMSO) δ 8.73-8.66 (m, 1H), 8.64 (s, 1H), 8.02 (dd, J=8.9, 3.4 Hz, 2H), 7.87-7.78 (m, 1H), 7.68-7.52 (m, 3H), 6.71 (s, 1H), 4.25 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Na].[O:2]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[N:3]1.Br[CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1>C1(C)C=CC=CC=1>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][CH2:19][CH2:18][O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:4]2[C:5]3[S:9][CH:8]=[CH:7][C:6]=3[O:2][N:3]=2)[CH:11]=1
Reactant: Oc1cccc(-c2noc3ccsc23)c1
Reactant: Fc1cccc(CNCCBr)c1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
Add dichloromethane to 3-thieno[2,3-d]isoxazol-3-yl-phenol (10 g, 0.046 mol) or the appropriately protected 3-thieno[2,3-d]isoxazol-3-yl-phenol as is known in the art, and stir with sodium hydroxide (1M; 28 mL) to form the sodium salt. Combine the sodium salt from 3-thieno[2,3-d]isoxazol-3-yl-phenol, (2-bromo-ethyl)-(3-fluorobenzyl)-amine (37.5 g, 0.161 mol) in toluene (100 mL) and heat (reflux) for 24 hours. Allow to cool, filter the reaction mixture and evaporate off the solvent to give the final, desired compound. Compound may be purified by distillation under reduced pressure.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH3:9][C:7]1[N:8]=[C:4]([N:1]2[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[N:2]2)[S:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C#CCCCc1ccccc1
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-azido-4-methylthiazole-5-carboxylate (5.31 g, 25.02 mmol) in tetrahydrofuran (50 mL) was added copper(I) iodide (4.76 g, 25.02 mmol), N,N-diisopropylethylamine (13.07 mL, 75.06 mmol) and 5-phenyl-1-pentyne (3.97 g, 27.52 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:4 ratio) to afford the title compound in 79% yield (7.04 g): 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.31-7.16 (m, 5H), 4.33 (q, J=6.0 Hz, 2H), 2.82 (t, J=9.0 Hz, 2H), 2.77-2.69 (m, 5H), 2.10-2.04 (m, 2H), 1.38 (t, J=6.0 Hz, 3H); MS (ES+) m/z 357.3 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=2)[C:8]([CH3:27])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[C:8]([CH3:27])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a round bottom flask was added methyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylate (2.30 g, 6.0 mmol), THF (20 mL), MeOH (30 mL), and 1M aqueous NaOH (25 mL). The reaction mixture was allowed to stir at rt overnight. The mixture was concentrated and 1M aqueous HCl was added until the solution became acidic. The mixture was filtered and the solid was dried to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (Compound I-6) (1.4 g, 64%). LCMS (FA): m/z=372.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23](O)=[O:24])=[C:5]([O:26][C:27]([F:30])([F:29])[F:28])[CH:4]=1)#[N:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:39]1C=CN=C1)=O.N>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([NH2:39])=[O:24])=[C:5]([O:26][C:27]([F:28])([F:30])[F:29])[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)O)=C(C)N2
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.477 mmol) of the compound from Example 37A are introduced into 5 ml of ethyl acetate and, after addition of 96.7 mg (0.596 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight (TLC check: insufficient reaction). Then 1 ml of DMF is added, and the mixture is stirred at room temperature for a further night (TLC check: complete conversion). The volatile components are removed in a rotary evaporator, and the residue is taken up in 4 ml of DMF. Then 663 μl of ammonia (28% by weight solution in water, 4.77 mmol) are added, and the reaction mixture is heated at 100° C. in a closed vessel overnight. After cooling, the solvent is removed under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 140 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[ClH:22]>ClCCl>[ClH:1].[ClH:22].[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccnc(Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: NC1CCN(c2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 199.9 %

Procedure:
To a solution of tert-butyl 1-(2-chloropyridin-4-yl)piperidin-4-ylcarbamate (1.00 g, 3.21 mmol) in dichloromethane (16 mL) was added HCl (2 M in diethylether, 8.02 mL, 16.0 mmol) and the reaction mixture was stirred at room temperature over night for 18 hours. The mixture was then filtered off and the white precipitate washed with dichloromethane and diethylether and dried to afford the title compound (913 mg, 99%) as a white solid. MS ISP (m/e): 212.1/214.1 [(M+H)+].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([S:31][CH3:32])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[C:20]([S:26][CH3:27])[CH:19]=2)[CH:15]=1)[CH2:11]O.C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([S:31][CH3:32])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[C:20]([S:26][CH3:27])[CH:19]=2)[CH:15]=1)[CH2:11][Br:34]
Reactant: BrC(Br)(Br)Br
Reactant: CSc1cc(COc2cc(CO)cc(OCc3cc(SC)cc(SC)c3)c2)cc(SC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1cc(COc2cc(CBr)cc(OCc3cc(SC)cc(SC)c3)c2)cc(SC)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 286.8 %

Procedure:
3,5-Bis-(3,5-dimethylthiobenzyloxy)benzyl alcohol (17.0 g, 0.033 mol) and carbon tetrabromide (14.2 g, 0.0043 mol) were dissolved in 100 ml of tetrahydrofuran. To this, triphenylphosphine (11.3 g, 0.043 mol) was added portionwise. at the temperature of 1.0 to 10° C. After completion of the addition, the mixture was stirred for 7 hours keeping the mixture at the same temperature. Then, the reaction mixture was poured into 300 ml of ice-water and the resulting mixture was extracted with chloroform. The extract was purified by means of chromatography, giving 7.0 g of 3,5-bis(3,5-dimethylthiobenzyloxy)benzyl bromide
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[ClH:23]>CC(O)C.[Pd]>[ClH:23].[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Yield: 60 %

Procedure:
1-Cyclopentyl-4-(4-nitrophenyl)piperidine (303) (6.5 g, 24 mmol) was dissolved in IPA (70 mL) and 2M HCl (aq) (18 mL), and 10% Pd/C (2 g) was added. The resulting mixture was agitated on Parr shaker under 50 psi hydrogen for 18 hours. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure to give 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (4.0 g, 14 mmol, 60% yield).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[C:5]([F:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1F)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 15.4 %

Procedure:
To a solution of the above crude Boc-Tyr(2-F)-OH (0.82 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.77 g, 2.11 mmol) and CMPI (0.81 g, 3.17 mmol) in THF (5 ml), TEA (1.18 ml, 8.44 mmol) was added under cooling with ice and stirred at room temperature for 23 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.21 g, 15%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[CH:7]=[CH:8][O:9][C:5]=2[CH:4]=1.[C-:12]#[N:13].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[O:9]1[C:5]2[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:11]=[CH:10][C:6]=2[CH:7]=[CH:8]1
Reactant: [C-]#N
Reactant: BrCc1ccc2ccoc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1ccc2ccoc2c1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
A mixture of 6-bromomethylbenzofuran (4.38 g, 0.021 mol), sodium cyanide (2.0 g, 0.041 mol), tetrabutylammonium bromide (0.42 g, 0.0013 mol), water (15 cm3) and dichloromethane (15 cm3) was stirred vigorously for 18 hr. The mixture was separated and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was extracted with petroleum ether (b.p. 60°-80° C.), and the solvent was removed to give benzofuran-6-acetonitrile (3.09 g, 0.0197 mol), 93.7%) as an oil, t.l.c./silica/toluene, RF 0.21.
Reaction SMILES: CC(C)([O-])C.[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:15][O:16][N:17]([CH3:26])[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].C1(C)C=CC=CC=1>CCOCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]([N:17]([O:16][CH3:15])[CH3:26])=[O:19])[CH2:21][CH2:22]2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CON(C)C(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CON(C)C(=O)C1CCN(c2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
A flask containing 2-(2′-di-tent-butylphosphine)biphenylpalladium(II) acetate (0.927 g, 2.003 mmol) and potassium tert-butoxide (1.798 g, 16.03 mmol) was flushed with nitrogen and then charged with 4-bromochlorobenzene (3.07 g, 16.03 mmol), N-methoxy-N-methylpiperidine-4-carboxamide (2.3 g, 13.35 mmol) and anhydrous toluene (25 mL). The resulting mixture was stirred under nitrogen at 100° C. for 1.5 h. After this time, the reaction mixture was cooled to room temperature, diluted with ether (200 mL), washed with water and brine, dried over MgSO4 and concentrated to yield a residue. The residue was purified by flash chromatography using a 120 g silica gel cartridge and an eluent gradient from 10:1 Hex/EtOAc to 2:1 EtOAc/Hex. The fractions containing the product were pooled and concentrated on a rotary evaporator to the title compound (2.2 g, 7.78 mmol, 58.3% yield) as a yellow-green solid. LC-MS: (Waters Sunfire C18 4.6 mm×50 mm). 283.19, [M+H]; tR=1.79 min; 4 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate. 1H NMR (400 MHz, CDCl3) δ ppm 7.13-7.21 (2H, m), 6.81-6.87 (2H, m), 3.72 (3H, s), 3.69 (1H, t, J=3.30 Hz), 3.66 (1H, t, J=2.86 Hz), 3.19 (3H, s), 2.70-2.82 (3H, m), 1.82-1.94 (4H, m).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([CH3:23])[CH:13]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:37]=[C:36]([Sn](C)(C)C)[CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][C:25]1[CH:37]=[C:36]([C:2]2[C:10]3[O:9][C:8]([NH:11][C:12]4[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([CH3:23])[CH:13]=4)=[N:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:35]=[CH:34][C:26]=1[CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: Cc1cc(Nc2nc3cccc(Br)c3o2)ccc1C(=O)N(C)C
Reactant: C[Sn](C)(C)c1ccc(CN2CCOCC2)c(F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cc(Nc2nc3cccc(-c4ccc(CN5CCOCC5)c(F)c4)c3o2)ccc1C(=O)N(C)C
Temperature: 150 °C
Reaction time: 1 h

Procedure:
0.1 g (0.267 mmol) 4-(7-bromo-benzooxazol-2-ylamino)-2,N,N-trimethyl-benzamide and 0.17 g (0.305 mmol) 4-(2-fluoro-4-trimethylstannanyl-benzyl)-morpholine are dissolved in 2 ml 1,2-dimethoxy-ethane and a stream of argon is bubbled through the mixture in order to exclude oxygen from the reaction mixture. Tetrakis (triphenylphosphine) palladium (0.020 g, 0.016 mmol) is added and the reaction mixture is stirred at 150° C. for 1 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc:MeOH=95:5; column chromatography followed by thick-layer chromatography) to afford the title compound. Rt=1.67 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 375 (M+1)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[CH2:20]([O:23][CH2:24][C:25]([CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:26])[CH2:21][CH3:22]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:27][C:25](=[O:26])[CH2:24][O:23][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: CCCOCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Yield: 150.2 %

Procedure:
A mixture of 7-formyl-6-(7 -hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (4.2 g.) and propoxyacetylmethylenetriphenylphosphorane (7.18 g.) in dry tetrahydrofuran (35 ml.) was heated at reflux under nitrogen for 18 hours. The solvent was removed in vacuo and the residue triturated with a mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate, allowed to stand at 0° C., filtered to remove triphenylphosphine oxide and the filtrate evaporated to dryness to give 6-(7-hydroxyheptyl)- 7-(3-oxo-4 -propoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane (8.6 g.), νmax 1620 cm-1, 1680 cm-1.
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O>>[S:11]1[CH:12]=[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:7])=[O:1])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=C(O)CCC(=O)c1csc2ccccc12
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1csc2ccccc12
Yield: 78 %

Procedure:
The γ-oxo-benzo[b]thiophene-3-butyric acid is coupled to L-proline with 1,1'-carbonyldiimidazole to give 1-[3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (78%) as a glass. As for Example 1, the preceding compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline as a glass (97%). Reaction with sodium thioacetate in ethanol gives the product (92%) of the Example as a glass.
Reaction SMILES: [O:1]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/I)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C([Li:22])CCC>CCCCCC>[O:1]([CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[CH:10]=[CH:11]/[Li:22])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: [Li]CCCC
Reactant: CCCCCC(/C=C/I)O[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
On the other hand, 442 mg (1.2 mmol) of 3-t-butyldimethylsiloxy-1-iodo-trans-1-octene was added to 2 ml of anhydrous hexane, and 1 ml (1.2 mmol) of a 1.2 M hexane solution of n-butyllithium was added. The mixture was stirred at -78° C for 30 minutes in an atmosphere of nitrogen to afford an anhydrous hexane solution of 3-t-butyldimethylsiloxy-1-lithio-trans-1-octene. The resulting solution was added dropwise to the anhydrous diethyl ether solution of copper pentylide prepared previously, and the mixture was stirred at -78° C for 30 minutes in an atmosphere of nitrogen to afford a solution of an organic copper lithium compound of the following formula ##STR20##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[NH:5][CH:6]([CH3:31])[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([C:18]#[N:19])[CH:17]=1)[N:14]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:13][CH2:12]2)=O)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:32])[NH:5][CH:6]([CH3:31])[CH2:7][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([C:18]#[N:19])[CH:17]=1)[N:14]([CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:25])[CH3:26])[CH2:13][CH2:12]2)[CH3:2]
Reactant: CCOC(=O)NC(C)C(=O)c1cc(C#N)c2c(c1)CCN2CCCO[Si](C)(C)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NC(C)Cc1cc(C#N)c2c(c1)CCN2CCCO[Si](C)(C)C(C)(C)C
Temperature: 27.5 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
A mixture of (2-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-7-cyano-2,3-dihydro-1H-indol-5-yl}-1-methyl-2-oxo-ethyl)-carbamic acid ethyl ester (IV) (10 g, 0.02 mole), toluene (80 ml), triethyl silyl hydride (5.57 g, 0.04 mol) and trifluoroacetic acid (1.36 g, 0.01 mole), was stirred at 25-30° C. for a period of 6 hours. The reaction mass was quenched with water (50 ml) and toluene layer was dried over sodium sulphate. The solvent was evaporated under reduced to give 6.7 g of (V) as oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:23])=[C:10]([C:12]2[NH:21][C:20](=O)[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[N:13]=2)[CH:11]=1>C(Cl)(Cl)Cl.CN(C=O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([F:23])=[C:10]([C:12]2[N:21]=[C:20]([Cl:3])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][N:18]=3)[N:13]=2)[CH:11]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc(Br)cc1-c1nc(Cl)c2nccnc2n1
Yield: 99.3 %

Procedure:
Thionyl chloride (371 mg, 3.11 mmol) was added to the stirred suspension of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 (200 mg, 0.623 mmol) in chloroform (5 mL) and dry DMF (100 μL). The reaction mixture was refluxed under nitrogen for 1 h (starting material gone by HPLC). The solvent was removed in vacuo. Then the residue was triturated in Et2O and filtered off to give 210 mg of the title product 106 as a yellow solid (LCMS analysis).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[C-:25]#[N:26].[K+]>CS(C)=O.C([O-])(O)=O.[Na+]>[C:25]([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:26]
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(CCl)ccn2)CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccnc(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 51.3 %

Procedure:
A solution of benzyl 4-(4-(chloromethyl)pyridin-2-yl)piperazine-1-carboxylate (5.0 g, 14.5 mmol) and KCN (2.8 g, 43.5 mmol) in DMSO (30 mL) was stirred at RT overnight, and then diluted with sat. NaHCO3 (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with H2O (50 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated to afford crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=1:1) to give benzyl 4-(4-(cyanomethyl)pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (2.5 g, 51%). MS (ES+) C19H20N4O2 requires: 336, found: 337[M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][CH2:9][C:10](O)=[O:11])[CH:7]=1.O.O.[Sn](Cl)Cl>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[Cl:16])[NH:13][C:10](=[O:11])[CH2:9][NH:8]2
Reactant: O=C(O)CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: O=C1CNc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
A solution of N-(5-bromo-4-chloro-2-nitrophenyl)glycine (0.255 g, 0.824 mmol) and tin (II) chloride dihydrate (0.560 g, 2.48 Aldrich, used as received) was refluxed for 3 h. It was then cooled to r.t. and allowed to stand overnight at r.t. The whim solid was filtered and dried to yield 0.038 g (18%) of pure title compound as white flakes; m.p. 230°-232° C.; 1H NMR (DMSO-d6): 3.732 (s, 2H), 6.371 (s, 1H), 6.830 (s, 1H), 6.912 (s, 1H), 10.437 (s, 1H). Extraction of the filtrate with ethyl acetate (30 mL) gave 0.136 g (68%) more product to get a combined yield of 81%.