Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of (34) (2.34 g, 4.71 mmol) in dry THF (40 ml) was added at 0° C. TBAF (5.2 ml, 5.2 mmol, 1 M solution in THF). The reaction mixture was allowed to warm up to room temperature and was then stirred for 16 h. The reaction was quenched by adding sat. NaCl solution (20 ml) and extracted with EtOAc three times. The combined organic layers were dried over MgSO4. The crude mixture was purified by chromatography on silica (EtOAc:petrol 7:3). Product (35) (1.4 g, 75%) was isolated as a colourless solid. 1H NMR (d6 DMSO) δ 2.02-2.39 (m, 2H, H-2′), 3.42-3.52 (m, 2H, H-5′), 3.84-3.88 (m, 3H, H-4′, CH2], 3.97-4.00 (m, 1H, H-3′), 5.02-5.09 (m, 2H, OH, ═CH2), (dd, J=1.9, 17.3 Hz, 1H, ═CH2), 5.73-5.82 (m, 1H, CH═), 5.94 (t, J=6.8 Hz, 1H, H-1′), 8.24 (s, 1H, H-6), 11.56 (s, 1H, NH). Mass (−ve electrospray) calcd for C12H16IN2O5, 394.0. found 393.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:28][C:29]2[C:34]([C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1>CO>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:28][C:29]2[C:34]([C:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:11][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc(CCN(Cc3ncc(C)cc3C)Cc3ncccc3C(C)(C)c3ccc(F)cc3)c2)cc1
Agent: On1nnc2ccccc21
Solvent: CO
Product: Cc1cnc(CN(CCc2c[nH]cn2)Cc2ncccc2C(C)(C)c2ccc(F)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of (3,5-dimethyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-{2-[1-{toluene-4-sulfonyl)-1H-imidazol-4-yl]-ethyl}-amine (87.3 mg, 0.143 mmol) in anhydrous MeOH (1.5 mL) was added HOBT (77.1 mg, 0.57 mmol). After stirring overnight the reaction mixture was concentrated. Purification by radial chromatography on silica gel using 5% MeOH/CH2Cl2 afforded COMPOUND 175 (36 mg, 55%) as a clear oil. 1H NMR (CDCl3) δ 1.65 (s, 6H), 1.97 (s, 3H), 2.20 (s, 3H), 2.53 (s, 4H), 3.30 (s, 2H), 3.37 (s, 2H), 6.63 (s, 1H), 6.88 (t, 2H, J=8.52 Hz), 7.04 (m, 3H), 7.30 (m, 1H), 7.61 (s, 1H), 7.93 (d, 1H, J=7.91 Hz), 8.05 (s, 1H), 8.55 (d, 1H, J=3.58 Hz). 13C NMR (CDCl3) δ 18.1, 18.2, 22.8, 31.4, 42.4, 53.3, 57.8, 58.8, 115.5, 115.8, 122.4, 124.1, 127.5, 127.6, 130.2, 132.1, 132.6, 134.5, 134.7, 139.2, 144.0, 145.4, 146.4, 146.5, 153.4, 158.5, 159.8. ES-MS m/z 458 [M+H]+. Anal. Calcd. for C28H32FN5.1.1 H2O.0.3 CH2Cl2: C, 73.49; H 7.05, N 15.30, Found: C, 70.02; H, 7.02; N, 14.87.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[OH:17][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[O:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(=O)O2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2CCC(O)O2)cc1

Procedure:
To a suspension of (±)-dihydro-5-(p-toluensulfonyloxymethyl)-2(3H)-furanone (example 57) (5.20 g, 19.26 mmol) in anhydrous toluene (125 mL) at -78° C. was added DIBAL (1.5 M in toluene, 13.5 mL, 20.22 mmol) dropwise. The solution was allowed to stir at -78° C. for 2 h. water was then added to the mixture and the reaction mixture was brought to rt. The mixture was filtered through a CELITE diatomaceous earth and the organic layer was collected, dried (MgSO4) and concentrated to give the title compound as a 1:1 mixture of cis and trans isomers (4.2 g, 80%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:7][N:6]=[C:5]([NH2:8])[N:4]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:11]1[C:15]2([CH2:20][CH2:19][CH:18]([NH:8][C:5]3[N:4]=[C:3]([C:2]([F:10])([F:9])[F:1])[NH:7][N:6]=3)[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1
Reactant: Nc1n[nH]c(C(F)(F)F)n1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1nc(NC2CCC3(CC2)OCCO3)n[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.3 %

Procedure:
To a solution of 5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine (12.19 g) and 1,4-dioxaspiro[4.5]decan-8-one (12.49 g) in acetic acid (180 mL) was added sodium triacetoxyborohydride (25.43 g), and the mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] and crystallized from diisopropyl ether to give the title compound as a colorless solid (9.88 g, 42%).
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:6]1)(=O)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1.[Sn](Cl)(Cl)(Cl)Cl>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[C:20]([O:19][C@H:8]1[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([C:31]2[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[O:6][CH:7]1[CH2:23][O:24][C:25](=[O:27])[CH3:26])(=[O:22])[CH3:21]
Reactant: CC(=O)OCC1OC(OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(C)cc1
Agent: [Ag+]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C)cc1[C@@H]1OC(COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 4 h
Yield: 76 %

Procedure:
To a mixture of (3S,4S,5R)-6-(acetoxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate (1.0 g, 2.56 mmol, mixture of 2-α and 2-β), 4-methoxytoluene (0.65 mL, 5.12 mmol) and silver trifluoroacetate (0.85 g, 3.84 mmol) in dichloromethane (5.0 mL) at room temperature was added a solution of tin(IV) chloride (7.7 mL, 1.0 M in dichloromethane) dropwise. The reaction solution was stirred under nitrogen for 4 hours and then it was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (eluent: hexanes/ethyl acetate) to give (3R,4R,5R,6S)-2-(acetoxymethyl)-6-(2-methoxy-5-methylphenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.88 g, 76%) as a orange oil: 1H NMR (CDCl3, 500 MHz) δ 7.18 (d, J=2.0 Hz, 1H), 7.07-7.05 (m, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.35 (t, J=9.5 Hz, 1H), 5.28 (t, J=9.0 Hz, 1H), 5.23 (t, J=9.5 Hz, 1H), 4.92 (d, J=9.5 Hz, 1H), 4.28 (dd, J=12.5, 5.0 Hz, 1H), 4.14 (dd, J=12.0, 2.5 Hz, 1H), 3.84 (ddd, J=10.0, 5.0, 2.5 Hz, 1H), 3.80 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.77 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10](F)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[C:10]([O:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH:9]=[C:8]([F:15])[CH:7]=2)#[N:2]
Reactant: N#Cc1cnc2cc(F)cc(F)c2c1O
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCC(Oc2cc(F)cc3ncc(C#N)c(O)c23)CC1
Temperature: 60 °C
Yield: 59 %

Procedure:
A mixture of 3-cyano-5,7-difluoro-4-hydroxyquinoline (4.12 g), 1-methylpiperidin-4-ol (2.6 g) and potassium tert-butoxide (6.72 g) in anhydrous tetrahydrofuran (250 ml) was stirred and heated at 60° C. for 2 hours. Acetic acid was added until pH6 was reached and then the solution was evaporated to dryness. The residue was dissolved in a mixture of dichloromethane and methanol (2:1) and the solution added to powdered silica gel (15 g). The suspension was evaporated to dryness and powder was packed into a preload cartridge. This was then chromatographed with an Isco Combiflash system and a Biotage 40M silica cartridge using a gradient elution of 0.6% to 30% ammonia (7.0M in methanol) in dichloromethane. The fractions containing the product were combined and evaporated. This gave the title compound as a white foam (3.55 g, 59%); NMR spectrum: (DMSOd6) 1.77 (m, 2H), 1.92 (m, 2H), 2.30 (s, 3H), 2.43 (m, 2H), 2.81 (m, 2H), 4.55 (m, 1H), 6.81 (m, 2H), 8.40 (s, 1H), Mass spectrum: M+H+ 302.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:4][CH:3]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: Fc1ccc(CCl)cc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Fc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 70.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.68 mmol) of tetrabutylphosphonium chloride, 1.00 g (6.92 mmol) of 4-fluorobenzyl chloride, and 2.80 g (20.7 mmol) of trichlorosilane were reacted at 130° C. for 4 hrs. The resulting mixture was distilled to give 1.19 g of (4-fluorobenzyl)trichlorosilane (82%).
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)#N.S(=O)(=O)(O)O.[C:36](=[O:39])(O)[O-:37].[Na+]>>[C:36]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)([OH:37])=[O:39]
Reactant: O=C([O-])O
Reactant: N#CC1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 3-[2-(2-cyanocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (130 mg) and conc. sulfuric acid (1.5 ml) was stirred at room temperature for 45 minutes. Then, the mixture was cooled in an ice-bath and treated with saturated aqueous sodium bicarbonate to make pH of the mixture to 2.0. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was crystallized from diethyl ether to give colorless crystals of 3-[2-(2-carboxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[N:3]=[CH:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-bromo-5-iodopyridine (3.00 g, 10.6 mmol), tert-butyl piperazine-1-carboxylate (1.71 g, 9.2 mmol), Pd2(dba)3 (337 mg, 0.368 mmol), and XantPhos (640 mg, 1.1 mmol) were taken up in PhCH3 (90 mL). The resulting mixture was stirred 24 h at r.t. and was diluted with EtOAc (100 mL) and water (150 mL). The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography to provide tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (4.01). LCMS-ESI+ (m/z): [M+H]+ calcd for C14H21BrN3O2: 342.08; found: 342.15.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH2:21])[CH2:8]1)(C)(C)C.[OH-].[Na+]>Cl.C(O)C>[NH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[O:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@H](Oc2cc(F)ccc2N)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(F)cc1O[C@H]1CCC[C@H](O)C1

Procedure:
A solution of 8.1 g 2-[trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-4-fluoro-phenylamine in 50 ml of HCl in ethanol (1.25 M) was stirred for 1 hour at rt. Sodium hydroxide solution (1 N) was then added to the reaction mixture resulting in a basic pH. This mixture was extracted with methylene chloride. The organic phase was dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:27]>CC(O)C>[NH2:27][C:7]1[C:6]2[N:5]([C:4]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[N:3][C:2]=2[Br:1])[CH:10]=[CH:9][N:8]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1nc(Br)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
(S)-Benzyl 2-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (20.54 mmol, 8.95 g) was suspended in 2-propanol (113 ml) in a pressure vessel. 2-propanol (50 ml) was cooled to −78° C. in a pre-weighed flask (with stopper and stirring bar) and ammonia gas (646 mmol, 11 g) was led through for 15 minutes. The resulting solution was added to the suspension in the pressure vessel. The vessel was closed and stirred at room temperature and a slight increase in pressure was observed. Then the suspension was heated to 110° C. which resulted in an increased pressure to 4.5 bar. The clear solution was stirred at 110° C., 4.5 bar overnight. After 18 h the pressure remained 4 bar. The reaction mixture was concentrated in vacuum, the residue was suspended in ethyl acetate and subsequently washed with water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 7.35 g of (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (86%).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17]O.[CH2:19]([N:21](CC)CC)C.[OH-].[Na+].[C-]#N.[K+]>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]([CH3:17])[C:19]#[N:21]
Reactant: OCCc1c[nH]c2ccc(Br)cc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: CC(C#N)c1c[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
The method of Bascop, S. I.; Laronze, J. Y.; Sapi, J. Synthetis of 2-aminopropyle-3-indole-acetic(propionic) acid derivatives. ARKIVOC 2003, 46-61, was followed. Methane sulphonyl chloride (MsCl, 0.55 mL, 2 equiv) was added to a stirred solution of 13 (3.2 mmol, 1 equiv), triethylamine (0.9 mL, 2 equiv) and anhydrous CH2Cl2 (20 mL) maintained at 0° C. The reaction mixture was then stirred for 30 min at 0° C. under N2, after which it was treated with 2M NaOH and extracted with CH2Cl2. The combined organic layer was washed with water, dried (anhydrous Na2SO4) and evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous DMSO (20 mL), KCN (3.25 mmol, 3 equiv) was added and the reaction mixture was heated at 100° C. in an oil bath for 1 h. It was diluted with a water-ice mixture, extracted with chloroform, the combined organic layer was washed with water, dried (anhydrous Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified by column chromatography with CHCl3 as eluting solvent and 14 was obtained. Yield: 75%; 1H NMR (300 MHz, DMSO-d6): δ 2.78 (t, J=15 Hz, 2 H), 3.58 (t, J=12 Hz, 2 H), 7.14-7.17 (m, 2 H), 7.20 (d, J=27 Hz, 1 H), 7.68 (s, 1 H), 11.01 (s, 1 H); MS (APCI): m/z 261.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[N:30])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[N:30])[C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:18][C:13]=2[NH:12][C:11](=[S:41])[CH2:10][N:9]=1
Reactant: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=O)CN=C2c1ccccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: N#Cc1cc2c(cc1OCCCN1CCOCC1)NC(=S)CN=C2c1ccccc1Cl

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-thione (Ik) was prepared by reacting 0.00057 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(3-(4-morpholinyl)propoxy)-2H-1,4-benzodiazepin-2-one (Ik) with Lawesson's reagent in a manner analogous to Example 38. MH+/Z=455.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=O.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([NH2:27])[CH3:26])[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([NH:27][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH3:26])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1cccs1
Reactant: CC(N)c1ccc(F)c(F)c1
Product: CC(NC(c1cccc([N+](=O)[O-])c1)c1cccs1)c1ccc(F)c(F)c1
Yield: 95 %

Procedure:
Following a similar procedure to that described in Example (1a), 3.03 g of 3-nitrophenyl thiophen-2-yl ketone and 2.52 g of 1-(3,4-difluorophenyl)ethylamine were reacted, to obtain 4.62 g of the title compound as a reddish orange oil.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH:1]1([C:6]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C1CC=CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopent-3-ene-1-carboxylic acid (9.63 g, 85.88 mmol) in 143 mL of degassed DMF was added potassium carbonate (14.24 g, 103.06 mmol) and benzyl bromide (11.24 mL, 94.47 mmol). The mixture was stirred for 2 hours at ambient temperature, and then poured into 150 mL of water and extracted with ethyl acetate. The extracts were washed with water and brine, and dried over sodium sulfate. Filtration and concentration under vacuum afforded benzyl cyclopent-3-ene-1-carboxylate as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[CH3:27].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(#N)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[CH:20][C:19]=1[CH3:27]
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: Cc1cc(B(O)O)ccc1F
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: CC#N
Product: Cc1cc(-c2cnccc2N2CCC(C(N)=O)CC2)ccc1F
Yield: 56 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), 4-fluoro-3-methylphenylboronic acid (16 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative tlc (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (15 mg, 56%), LC-MS (ESI 3.5 min) Rt 1.46 min, m/z 314 (100%, [M+H]+); m/z (ESI) C18H21FN3O requires 314.1663 found [M+H]+ 314.1658.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH2:29][C:30]#[C:31][CH3:32])[C@H:3]([O:22]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][C@H:7]1[OH:21]>C(O)(=O)C.O.C1COCC1>[CH3:1][C:2]([CH3:33])([CH2:29][C:30]#[C:31][CH3:32])[C@H:3]([OH:22])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][C@H:7]1[OH:21]
Reactant: CC#CCC(C)(C)[C@@H](/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC#CCC(C)(C)[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O

Procedure:
290 mg. of (13E)-(11R,15R)-16,16-dimethyl-11-hydroxy-9-oxo-15-(tetrahydropyran-2-yloxy)-13-prosten-18-ynoic acid is agitated for 16 hours at room temperature with 8 ml. of a mixture of glacial acetic acid/water/THF (65/35/10), evaporated under vacuum, and the residue purified by column chromatography on silica gel. With methylene chloride/5% methanol, 185 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]([NH2:26])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:23]([NH:26][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:24][CH3:25])[CH3:22]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CCC(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC(C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), butan-2-amine (193 mg, 2.64 mmol, 6.00 equiv), potassium carbonate (181.6 mg, 1.32 mmol, 3.00 equiv), toluene (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 109 mg (crude) of methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate as yellow oil.