Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FS([C:5]([F:10])([F:9])C(O)=O)(=O)=O.[OH:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:14]>C(#N)C.[Cu]I>[F:9][CH:5]([F:10])[O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:14]
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO)c1
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 13 %

Procedure:
2-(Fluorosulphonyl)difluoroacetic acid (0.239 mL, 2.31 mmol) was added dropwise, with stirring, to a degassed mixture of methyl 3-{[(1S)-2-hydroxy-1-methylethyl]oxy}-5-[(phenylmethyl)oxy]benzoate (0.73 g, 2.31 mmol) and copper (I) iodide (88 mg, 0.46 mmol) in acetonitrile (10 mL) at 45° C. The reaction was stirred at 45° C. for 24 hours. The solvent was removed in vacuo and ethyl acetate (30 mL) added. The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with a gradient of 0-30% ethyl acetate in isohexane, to give the desired compound (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:29]([F:32])([F:31])[F:30])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([CH3:28])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:29]([F:31])([F:30])[F:32])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:28])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoate (7 g, 14.59 mmol, 1.00 equiv), methanol (100 mL), water (100 mL), sodium hydroxide (1.75 g, 43.75 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 2×50 mL of ethyl acetate and the aqueous layers combined. The pH value of the solution was adjusted to 1-2 with hydrogen chloride aq. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 5.1 g (77%) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH:13]=[CH2:14])[CH:7]=[CH:8][N:9]=2)[N:4]=1.Cl.[CH3:16][NH2:17].CC(O)=O>CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][NH:17][CH3:16]
Reactant: CN
Reactant: C=Cc1ccnc2ccc(OC)nc12
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CNCCc1ccnc2ccc(OC)nc12
Yield: 18.6 %

Procedure:
A solution of 2-methoxy-8-vinyl-[1,5]naphthyridine (prepared as in WO 02/08224; 0.28 g, 1.5 mmol) in MeOH (6 mL) was treated with methyl amine hydrochloride (0.1 g, 1 eq.) and heated in a sealed flask at reflux for 5 h. AcOH (0.9 mL) was added and the mixture heated at reflux overnight. The mixture was concentrated in vacuo, taken up in aq. ammonia and extracted with DCM/MeOH (9:1). The combined org. extracts were dried over MgSO4 and concentrated. The residue was purified by FC (DCM/MeOH 9:1+1% NH4OH) to give the title amine as a brown oil (0.06 g, 19% yield).
Reaction SMILES: [CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CO.C(O)C.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCc1ccc(CCC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Yield: 93.1 %

Procedure:
8- (p-pentylcinnamoyl) amino-2- (5-tetrazolyl) -1,4-benzodioxane (216 mg; synthesized in example 2(1)) and palladium-carbon (50 mg; content 5%) were suspended in a mixed solvent (6 ml) of methanol, ethanol and ethyl acetate (1:1:1). In an atmosphere of hydrogen, the suspension was stirred for 90 min at room temperature. After stirring, the suspension was filtered through celite. The filtrate was condensed under reduced pressure. The residue was purified by column chromatography on silica gel (methylene chloride: methanol=19:1) to give the title compound (202 mg) having the following physical data:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[N:12][C:11]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]2=3)[CH2:4][C@@H:3]1[CH2:22][NH:23]C(=O)OCC1C=CC=CC=1>CO.[Pd].[O-2].[Mn+4].[O-2]>[NH2:23][CH2:22][C@@H:3]1[C@H:2]([OH:1])[CH2:6][N:5]([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[N:12][C:11]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:10]2=3)[CH2:4]1
Reactant: COc1ccc2ncc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2n1
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A solution of phenylmethyl [((3S,4S)-4-hydroxy-1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (1.0 g, 2.2 mmol) in methanol was treated with 10% Pd/C (0.44 g) and shaken under 15 psi at room temperature for 2 hours. Pd was filtered through Celite®, the filtrate was concentrated. The residue was redissolved in DCM (20 mL) and methanol (5 mL), treated with manganese(IV) oxide (561 mg, 6.6 mmol), and stirred at room temperature for 2 hours. Solid was filtered and filtrate was concentrated to give product (0.6 g, 85%).
Reaction SMILES: [C:1]([C@@H:4]([NH:13][C@@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=2[O:16][CH2:15]1)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([OH:3])=[O:2].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+].[I-].[K+]>CN(C)C=O.O>[CH2:34]([O:2][C:1]([C@@H:4]([NH:13][C@@H:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=2[O:16][CH2:15]1)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:3])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCC2CCCCC2)C(=O)O)COc2ccccc21
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCC2CCCCC2)C(=O)OCc2ccccc2)COc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
In 10 ml of N,N-dimethylformamide is dissolved 0.25 g of tert-butyl 3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 50, and benzyl bromide (0.14 g), sodium bicarbonate (0.7 g) and potassium iodide (0.05 g) are added to the solution. The reaction solution is stirred at room temperature for 6 hours and diluted with water (100 ml) and extracted with ethyl acetate. The extract is washed successively with 1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 0.25 g of tert-butyl 3(S)-[1(S)-benzyloxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]([O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6])C.[OH-].[Li+].Cl>O1CCOCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH:5]([CH3:6])[C:4]([OH:14])=[O:3])[CH:9]=1
Reactant: CCOC(=O)C(C)Oc1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(Oc1cccnc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of 2-(pyridin-3-yloxy)-propionic acid ethyl ester, 320 mg (1.6 mmol) in 10 mL of dioxane was added a solution of 190 mg (8.0 mmol) of lithium hydroxide in 10 mL of water. The reaction mixture was stirred for three hours, acidified to pH=1 with 5 N HCl and concentrated to dryness to yield the crude desired product which was carried on without further purification. MS (IS) 168.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(C)coc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1coc2cc(C(=O)O)ccc12
Reaction time: 8 h
Yield: 81.8 %

Procedure:
Methyl 3-methyl-1-benzofuran-6-carboxylate (720 mg, 3.78 mmol) is dissolved in MeOH (10 ml), treated with 2N NaOH (2.27 ml, 4.5 mmol) and stirred overnight. The volatiles are removed in vacuo, the residue is dissolved in H2O (5 ml) and the pH is adjusted to 3 with concentrated HCl. The mixture is stirred overnight and the resulting solid is filtered to afford 545 mg (82%) of 3-methyl-1-benzofuran-6-carboxylic acid as a white solid. HRMS (FAB) calcd for C10H8O3+H: 177.0552, found 177.0551 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl-].[Cl-].[Cl-].[Al+3].C(=O)([O-])[O-].[Na+].[Na+].[Br:22]Br.Cl>>[Br:22][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH2:2][C:1]2=[O:11]
Reactant: BrBr
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al+3]
Product: O=C1CCCc2c(Br)cccc21
Temperature: 70 °C
Yield: 27.9 %

Procedure:
To prepare this compound, 1-tetralone (10.2 g, 70 mmol) was added dropwise to a slurry of aluminum trichloride (23.3 g, 175 mmol) heated to 70° C. in a 3-neck flask with an outlet tube connected to a 2 M sodium carbonate solution. The slurry was stirred with a spatula. After the addition of 1-tetralone, the slurry was removed from heat and allowed to cool to room temperature. Bromine (12.3 g, 77 mmol) was added dropwise over 15 minutes. After that addition was complete, the slurry was heated at 80° C. for 10 minutes, then it was poured into a mixture of 200 grams of ice and 25 mL concentrated HCl. The 3-neck flask was rinsed with water and that rinse water was also added to the ice and slurry solution. That solution was extracted twice with ether (200 mL each) and those two extracts were combined. The combined ether extract was washed sequentially with water (50 mL), saturated sodium bicarbonate (25 mL), and brine (100 mL), and then was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil. The oil was subjected to flash chromatography (12% THF/hexanes), and the resultant product was recrystallized from hexanes to afford 4.4 g (27%) of 5-bromo-3,4-dihydro-2H-naphthalen-1-one. 1H NMR (500 MHz, CDCl3) δ 8.03 (dd, J=7.7, 1.2, 1H), 7.75 (dd, J=7.7, 1.2, 1H), 7.20 (t, J=7.8, 1H), 3.03 (t, J=6.2, 2H), 2.66 (t, J=6.5, 2H), 2.15-2.20 (m, 2H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH3:17])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.O>C(O)(=O)C>[Br:1][CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH3:3])[CH3:17])=[CH:13][CH:12]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCCN(C)C)cc1
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCOc1ccc(C(=O)CBr)cc1
Temperature: 24 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
2-(Dimethylamino)ethyl chloride hydrochloride (3.49 g, 23.2 mmol, 1.1 eq.) was added to a solution of 4′-hydroxyacetophenone (3.00 g, 22.0 mmol, 1 eq.) in acetone (100 mL), followed by the addition of potassium carbonate (9.12 g, 66.0 mmol, 3 eq.). The reaction mixture was heated under reflux overnight, cooled, and filtered; and the filtrate was concentrated and water (50 mL) was added, forming a cloudy solution. Hydrochloric acid (0.1N, 20 mL) was added, and the resulting clear solution was extracted three times with ethyl acetate. The aqueous phase was made basic with aqueous sodium hydroxide, forming a cloudy mixture, which was extracted with ethyl acetate (5×50 mL), then the ethyl acetate layer dried over magnesium sulfate and the ethyl acetate evaporated to give 4′-[2-(dimethylamino)ethoxy]acetophenone (2.90 g) as a light yellow oil, with identity and purity verified by LC-MS. Bromine (1.62 g, 10.1 mmol, 1.4 eq.) was added dropwise to a solution of the 4′-[2-(dimethylamino)ethoxy]acetophenone (1.5 g, 7.24 mmol) in acetic acid (5 mL) and the reaction mixture stirred at 24° C. for 3 hours, giving a dark red solution. The reaction mixture was cooled, water (5 mL) was added, and the mixture was lyophilized overnight. The crude 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone was purified by preparative HPLC, followed by lyophilization of the appropriate fractions, to give 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone (0.7 g) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](B(O)O)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cc2c(cc1-c1ccc(F)cc1)OCO2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2cc3c(cc2-c2ccc(F)cc2)OCO3)cc1
Yield: 75.8 %

Procedure:
Under nitrogen, 500 mg of Pd(PPh3)4 was added to a stirred solution of 1.55 g (6.0 mmol) of [6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]boronic acid (Step 2) and 1.09 g (4.62 mmol)of 4-bromobenzenesulfonamide (Lancaster) in 30 mL of toluene, 20 mL of ethanol, and 15 mL of 2M Na2CO3. After vigorous stirring at reflux for 6hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate. The resulting solution was washed with water and dried over Na2SO4. Purification by silica gel chromatography (MPLC)with ethyl acetate/hexane (3:7) gave 1.3 g (76%) of 4-[6-(4-fluorophenyl)-1,3-benzodioxol-5-yl]benzenesulfonamide as a colorless solid: mp 191.0°-192.5° C.; NMR (CDCl3) δ 4.80 (s, 2H), 6.06 (s, 2H), 6.83-6.92 (m, 4H), 6.97-7.06 (m, 2H), 7.20(d, J=8.5 Hz, 2H), 7.74(d, J=8.5 Hz, 2H). MS (FAB): m/e 372 (H+H). Anal. Calc'd for C19H14FNO4S: C, 61.45; H, 3.80; N, 3.77. Found: C, 61.48; H, 3.92; N, 3.68.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:21]1[C:22]2[C:17](=[CH:16][C:15]([CH:14]=[CH:13][C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]4)=[CH:24][CH:23]=2)[CH2:18][CH2:19][NH:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2cc(C=Cc3ccc4c(c3)CCNC4)ccc2c1

Procedure:
A solution of Example 42I (2.28 g, 0.55 mmol) in 1:1 dichloromethane:TFA (10 mL) at room temperature was stirred for 1 hour, then concentrated to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH:12]1([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:19](=[O:20])[CH2:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)CC1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cccc(CCNC(=O)CC2CCCCC2)c1
Temperature: 30 °C
Yield: 72.4 %

Procedure:
A stirred mixture of 20 g of 3-methoxy-benzeneethanamine and 15.2 g of cyclohexylacetic acid was heated at 190°-200° C. under an inert atmosphere for 45 minutes and was then cooled to 30° C. The product was dissolved in ethyl acetate and the solution was washed successively with N sodium hydroxide solution, N hydrochloric acid and water and was evaporated to dryness. The 29 g of oil residue was crystallized from petroleum ether (b.p.=40°-70° C.) and the product was dried to obtain 21.3 g of N-[2-(3-methoxyphenyl)-ethyl]cyclohexane-acetamide in the form of a white solid melting at 74° C.
Reaction SMILES: [C:1]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]N1C(=O)CCC1=O)=O)=[O:23])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.[CH2:40]([NH2:43])[C:41]#[CH:42]>CN(C=O)C>[C:1]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH:43][CH2:40][C:41]#[CH:42])=[O:32])=[O:23])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1
Reactant: O=C(CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: C#CCN
Solvent: CN(C)C=O
Product: C#CCNC(=O)CCCCCNC(=O)CCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 8 h

Procedure:
To a stirred solution of 6-((6-((Biotinoyl)amino)hexanoyl)amino)hexanoic acid, succinimidyl ester (biotin-NHS ester) (0.2 g, 0.35 mmol) in dry DMF (5 ml), propargyl amine (0.04 ml, 0.6 mmol) was added. A white precipitate formed within 15 min and the mixture was stirred overnight. The solvent was removed in vacuo and the compound was dissolved in CHCl3. Next the CHCl3 was slowly added to a stirred solution of hexane, forming a white precipitate, which on drying afforded 0.15 g (83%). Mass Spect. (FAB) MW 508 [M+]; NMR assigned. Crisp, G. T.; Gore, J. Syn. Comm. 1997, 27, 2203-2125
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(C(=NO)N)[CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH:26]4[CH2:28][CH2:27]4)[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCN12
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(C4CC4)no3)c2[C@@H]2CCN12
Reaction time: 2 h

Procedure:
15.0 g (42 mmol) of 1-[[(S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-1-yl]carbonyl]imidazole are dissolved in 60 ml of N,N-dimethylformamide, whereupon the solution is treated with 4.60 g (46 mmol) of cyclopropanecarboxamidoxime and the mixture is heated to 100° for 2 hours. The mixture is evaporated to dryness, the residue is treated with 50 ml of acetic acid and the mixture is stirred at 115° for 2 hours. After evaporation of the solvent the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there is obtained (S)-8-chloro-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of melting point 140°-142°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (9.41 g, 0.048 mol) in dichloromethane (200 mL) at room temperature was added iPr2NEt (14.1 g, 0.110 mol), followed by MsCl (5.5 g, 0.048 mol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (1:1 hexane:ethyl acetate). The desired compound was obtained as an oil (11.06 g, 86%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=O)[CH:5]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CC(C)c1cc(=O)[nH]c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Cl)nc2ncccc12
Yield: 79 %

Procedure:
A solution of 4-isopropyl-1,8-naphthyridin-2(1 H)-one (800 mg, 4.3 mmol) and 475 L of POCl3 in toluene were reacted as outlined in Scheme 1 to give the desired 2-chloro-4-isopropyl-1,8-naphthyridine (690 mg, 79%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.41 (d, J=6.74 Hz, 6 H) 3.68 (dq, J=7.03, 6.84 Hz, 1 H) 7.38 (s, 1 H) 7.52 (dd, J=8.35, 4.25 Hz, 1 H) 8.44 (dd, J=8.50, 2.05 Hz, 1 H) 9.09 (dd, 1 H).