Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([OH:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2onc(O)c2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1noc2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A mixture of 5-nitro-1,2-benzisoxazol-3-ol (3.90 g, 0.0220 mol) and potassium carbonate (4.17 g, 0.0300 mol) in N,N-dimethylformamide is stirred for 30 minutes, treated with methyl bromoacetate (3.96 g, 0.0260 mol), stirred overnight at room temperature, and poured into an acidic ice-water mixture. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and a (1:1) to (4:1) methylene chloride/hexanes gradient gives the title product as a white solid (2.80 g, mp 72-73.5° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23](Cl)=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[O:33][C:34]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:35]=2[N:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:1]([O:5][C:6](=[O:30])[NH:7][C:8]([CH3:29])([CH3:28])[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[N:24][C:23]([C:38]2[CH:39]=[CH:40][C:34]4[O:33][C:32]([NH2:31])=[N:36][C:35]=4[CH:37]=2)=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(Cl)nc3c2)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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(c2cnc3ccc(-c4ccc5oc(N)nc5c4)nc3c2)CC1
Yield: 37.2 %

Procedure:
Tert-butyl(1-(4-(6-chloro-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (20) (190 mg, 0.44 mmol, 1.0 eq) and (2-aminobenzo[d]oxazol-5-yl)boronic acid (94 mg, 0.53 mmol, 1.2 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). To this mixture, Pd(PPh3)4 (51 mg, 0.044 mmol, 0.1 eq) and sodium carbonate (140 mg, 1.32 mmol, 3.0 eq) were added sequentially. The resulting mixture was heated at reflux for 2 h with stirring under an argon atmosphere. The reaction was complete based on TLC analysis. The reaction mixture was concentrate in vacuo, and purified by silica gel column chromatography (1-5% MeOH—CH2Cl2) to afford the desired product, tert-butyl(1-(4-(6-(2-aminobenzo[d]oxazol-5-yl)-1,5-naphthyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (D-21) (87 mg, 37.2%) as a yellow solid. ESI-MS m/z: 532.22[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14]([C:17](=[CH:23]N(C)C)[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH3:15]>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[CH:23]=[N:13][N:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=2)[C:14]=1[CH3:15])=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A stirred solution of 44.0 grams (0.21 mole) of 3-chloro-5-trifluoromethylpyridin-2-ylhydrazine and 38.6 grams (0.21 mole) of ethyl 2-acetyl-3-dimethylaminoacrylate, prepared by the method of J. R. Beck et al., J. Het. Chem., 24, 693 (1987), in 1000 mL of ethanol was heated at reflux for five hours. After this time, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a residual oil. The oil was taken up in methylene chloride and washed in succession with two 100 mL portions of aqueous 10% hydrochloric acid, an aqueous solution saturated with sodium bicarbonate, and water. The organic layer was dried and filtered. The filtrate was concentrated under reduced pressure, yielding 48.9 grams of 4-ethoxycarbonyl-5-methyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36](O)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccsc2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccsc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (250 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (187 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (131 mg) and triethylamine (638 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 58) (233 mg) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 93.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (50.1 g) in N,N-dimethylacetamide (550 ml) was added sodium hydride (10.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, to the reaction mixture was added dropwise a solution of 4-fluoronitrobenzene (42.2 g) in N,N-dimethylacetamide (100 ml) with stirring at the same temperature, and the resulting mixture was furthermore stirred at room temperature overnight. After stirring, to the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (13:7) as the eluent to afford the title compound (75.1 g, yield: 93%) as a pale yellow solid.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:9]=[C:10]([NH:13][C:14]([C:16]2[C:21]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:20][CH:19]=[C:18]([CH3:29])[N:17]=2)=[O:15])[S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[OH:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([C:16]2[C:21]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:20][CH:19]=[C:18]([CH3:29])[N:17]=2)=[O:15])[S:11][CH:12]=1
Reactant: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C(C)(C)O[SiH2]C(C)(C)C)cs2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(CO)cs2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of 40 mg (0.088 mmol) of 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid [4-(tert-butyl-dimethyl-silanyloxymethyl)-thiazol-2-yl]-amide in 1 ml of methylene chloride was added 200 mg (1.75 mmol, 20.0 equiv.) of Trifluoroacetic acid. After stirring for 2 h at room temperature, saturated sodium carbonate solution was added, and the pH was adjusted to 8. The aqueous phase was extracted three times with methylene chloride. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vaccuo. The residue (28 mg, yellow solid) was triturated with Diisopropyl ether, filtered and dried to yield the title compound (17 mg, 57%) as a light yellow solid, MS (ISP): m/e=343.1 (M+H+).
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)CC1)=O)(C)(C)C.[C:31]1([C:37]2([OH:43])[CH2:42][CH2:41]N[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:14][N:11]3[CH2:39][CH2:38][C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([OH:43])[CH2:42][CH2:41]3)=[CH:20][CH:19]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Reactant: OC1(c2ccccc2)CCNCC1
Product: OC1(c2ccccc2)CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 269 is synthesized from Intermediate C and 4-phenyl-piperidin-4-ol according to General Method K. (LC/MS method 16: ES+ m/z 403.4 [M+H]+, Rt=2.68 min)
Reaction SMILES: [OH:1][CH:2]([CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14](=S)[NH:15][N:16]=1.O.[NH2:24][NH2:25]>>[NH:24]([C:14]1[N:15]=[N:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]([OH:1])[CH2:18][NH:19][CH:20]([CH3:22])[CH3:21])=[CH:12][CH:13]=1)[NH2:25]
Reactant: CC(C)NCC(O)COc1ccccc1-c1ccc(=S)[nH]n1
Reactant: NN
Solvent: O
Product: CC(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-3(2H)-pyridazinethione (1.5 g, 0.005 mole) and hydrazine hydrate (30 ml) was heated under reflux in an atmosphere of nitrogen for 90 minutes. Excess of hydrazine hydrate was removed under reduced pressure to give 3-hydrazino-6-[2-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-pyridazine as an oil which was converted into an amorphous citrate (2 g, 83%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH2:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)[CH3:5].O>CS(C)=O>[CH2:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][C:1]#[N:2])=[CH:8][CH:7]=1)[CH3:5]
Reactant: [C-]#N
Reactant: CCc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of 4-ethylbenzyl alcohol (2.72 g, 20 mmol, purchased from Aldrich) and 50 ml of 47% hydrobromic acid (purchased from Wako Junyaku Kogyo) was stirred vigorously for 30 minutes at room temperature. The reaction mixture was extracted with hexane to give 3.98 g of 4-ethylbenzyl bromide as a colorless oil. Then to a hot solution (50° C.) of sodium cyanide (1.96 g, 40 mmol) in 20 ml of dimethyl sulfoxide was added the above 3.98 g of 4-ethylbenzyl bromide and the mixture was stirred for 3 hours at ambient temperature. To the resultant reaction mass was added water and extracted with hexane. The solvent was removed to give 2.70 g (yield: 93.1%) of 4-ethylphenylacetonitrile as a pale yellow oil.
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C:15](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][O:13][C@@H:12]([CH3:22])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]>C(O)C.[Pd]>[O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][O:13][C@@H:12]([CH3:22])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C=C1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@H]1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 55.7 %

Procedure:
A solution of (2R,4R)-4-t-butyldimethylsiloxymethyl -5-ethoxycarbonylmethylene-2-methyl-1,3-dioxane (17.0 g) in ethanol (170 ml) was shaken under hydrogen (3 atm) with 10% palladium on carbon at room temperature for 1.5 hours. After removal of the catalyst by filtration, the solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (500 g) with a mixture of n-hexane and ethyl acetate (20:1) as an eluent to give (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5 -ethoxycarbonylmethyl-2-methyl-1,3-dioxane (9.52 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17]>C(O)(C)C>[CH3:10][O:11][C:12]([C:13]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH:13]([C:12]([O:11][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19]
Reactant: CCOC(N)=CC(=O)OC
Reactant: O=Cc1ccccc1F
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2ccccc2F)C1C(=O)OC
Yield: 59 %

Procedure:
Heating a solution of 6.3 g of 2-fluorobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 50 ml of isopropanol for 8 hours yields 2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 180° C (isopropanol). Yield: 59% of theory.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:8]=1>CO.C(#N)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[C:9]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:18])[F:19])[N:8]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: COCCN
Solvent: CO
Solvent: CC#N
Product: COCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2-methoxyethanamine (59 μl, 0.69 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (66 mg, 0.25 mmol) in acetonitrile (2 mL). The reaction was stirred at rt over night. The reaction mixture was concentrated in vacuo and the crude was purified by preparative HPLC to give the title compound as a solid, 43 mg (57%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cc(CO)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CO)ccc1OC(C)=O
Reaction time: 1 h

Procedure:
A partial solution of 4-hydroxy-3-methoxybenzyl alcohol (1.23 g, 8 mmol), triethylamine (810 mg, 1.12 mL, 8 mmol) and 32 mL of dry CH2Cl2 was chilled in an ice bath. To the cold mixture was added dropwise acetyl chloride (628 mg, 570 μL, 8 mmol). The mixture was stirred at ice bath temperature 1 for one hour. Stirring at room temperature was allowed to take place overnight. The reaction mixture was diluted with CH2Cl2 and extracted with 1N HCl, water and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Column chromatography on silica gel using CH2Cl2/MeOH (98:2, v/v) gave 548 mg (35%) of CO as a clear oil: Rf=0.22 (hexanes/ethyl acetate, 6:4 v/v); 1HNMR (CDCl3) δ 7.00 (d, 4J=1.5 Hz, 1H), 6.99 (d, 3J=8.5 Hz, 1H), 6.89 (dd, 3J=8.0 Hz, 4J=1.5 Hz, 1H), 5.27 (s, 2H), 4.66 (s, 2H), 3.83 (s, 3H) and 2.30 (s, 3H). Exact mass (FAB+) calculated for C10H12O4[M+] 196.0736. found 196.0739.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][C:34]([C:37]([O:39]C)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(COc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 60 °C
Yield: 69.2 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (106 mg, 0.16 mmol) in methanol (6 mL) was added a solution of NaOH (30 mg, 0.75 mmol) in water (3 mL). The mixture was heated at 60° C. for 5 h, evaporated to remove methanol, cooled to room temperature, and acidified to “pH” 2 with HCl aq. The precipitate was collected and dried to give the title compound as a white solid (70 mg). m/z (M+H)+: 617
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14][CH2:13][NH:12]3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]Br)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH:11]3[CH2:16][CH:15]([CH:17]=[O:18])[CH2:14][CH2:13][N:12]3[CH2:35][CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CCNC(c2nc3c(Cl)cccc3s2)C1
Reactant: COc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCC(C=O)CC2c2nc3c(Cl)cccc3s2)cc1
Temperature: 25 °C

Procedure:
Mix [2-(4-chlorobenzothiazolyl)](4-piperidinyl)methanone.CF3CO2H (9.19 mmol), 2-(4methoxyphenyl)ethyl bromide (2.07 g, 9.64 mmol), potassium carbonate (3.33 g, 24.1 mmol) and dimethylformamide (35 mL) and heat at 90° C. overnight. Cool to room temperature and partition between a 2:1 mixture of ethyl acetate/toluene and water. Separate the aqueous phase and wash the organic phase with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1C=CC=CC=1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:7][N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: ON=C(Cl)c1cccc(Cl)c1
Reactant: C#CC(C)O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)c1cc(-c2cccc(Cl)c2)no1
Temperature: 0 °C

Procedure:
3-Chloro-benzohydroximoyl chloride (e.g. Kim, Jae Nyoung; Ryu, Eung K; J. Org. Chem. (1992), 57(24), 6649-50) (2.84 g, 14.8 mmol) was suspended in benzene (50 ml) and cooled to 0° C. 3-Butyn-2-ol (2.10 g, 29.9 mmol) and triethylamine (1.89 ml, 26.7 mmol) were added. The mixture was heated to 60° C. for 1.5 houes, cooled and diluted with benzene and 1N aqueous hydrochloric acid. After stirring, the separated benzene layer was evaporated to dryness and the crude purified via flash chromatography over silica using heptane/ethyl acetate=5/1 giving after drying in vacuo the title compound (0.49 g, 15%). 1H NMR (CDCl3), δ (ppm): 1.64 (d, 3 H), 5.07 (dq, 1 H), 6.50 (s, 1 H), 7.40 (m, 2 H), 7.68 (m, 1 H), 7.79 (m, 1 H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]=[C:20]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21]P(=O)(OC)OC>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:21][C:20](=[O:19])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(=O)CP(=O)(OC)OC
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Product: CCCCCCC(=O)C=Cc1ccc(OCc2ccccc2)c(OC)c1
Yield: 72.7 %

Procedure:
By following the procedure as in Reference Example 1(a) using 1.2 g of 4-benzyloxy-3-methoxybenzaldehyde and 1.53 g of dimethyl 2-oxooctylphosphonate, 1.27 g of 1-(4-benzyloxy-3-methoxyphenyl)-1-nonen-3-one was obtained. Melting point 78°-81° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)[CH3:2].Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:31])[O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[OH:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][CH:5]([CH2:4][N:3]([CH2:1][CH3:2])[CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]4[CH:25]=[CH:26][C:27](=[O:31])[O:28][C:29]=4[CH:30]=3)[O:10][C:9]=2[CH:11]=1
Reactant: CCNCC1COc2ccc(O)cc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc2ccc(=O)oc2c1)CC1COc2ccc(O)cc2O1
Temperature: 94 °C
Yield: 13.5 %

Procedure:
N-Ethyl-2,3-dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (2.11 g, 13.1 mmole), 7-(3-chloropropoxy)coumarin (3.44 g, 14.4 mmole), diisopropylethylamine (11 ml, 63.2 mmole) and sodium iodide (1.98 g, 13.2 mmole) were combined in 175 ml of DMF and heated at 94° C. for 2 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue column chromatographed on silica gel using first 0.5% methanol/dichloromethane and then 1.5% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum and the residue redissolved in dichloromethane and boiled on a hot plate, the dichloromethane gradually being replaced with isopropanol. 4N HCl/isopropanol (4 ml) was added and the title compound was collected by filtration. A second recrystallization from isopropanol yielded 0.73 g of white solid, monohydrochloride, m.p. 208°-215° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:29][CH:28]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:23][N:37]=[C:26]([C:27]4[CH:28]=[CH:29][C:30]([S:33]([NH2:34])(=[O:35])=[O:36])=[CH:31][CH:32]=4)[N:25]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)cc4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (146 mg, 58%). MS (ISP) 500.3 [(M+H)+]; mp 290° C.