Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][C:27]([NH:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]([NH:29][C:27](=[O:28])[CH2:26][O:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)c1cc2cccc(O)c2o1
Reactant: CC(C)NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C(=O)c1cc2cccc(OCC(=O)NC(C)C)c2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.5 %

Procedure:
To a solution of (7-hydroxy-2-benzofuranyl)(5-methyl-3-phenyl-4-isoxazolyl)methanone (example 4) (100 mg, 0.31 mmol) in DMF (5 mL) was added N-(chloroacetyl)isopropylamine (47 mg, 0.34 mmol) and potassium carbonate (173 mg, 1.25 mmol) and the reaction mixture was stirred at room temperature for 4 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 1:1) afforded the title compound (37 mg, 28%) as a white solid. MS m/e: 419.3 [M+H]+.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[S:10](=O)(=[O:13])([OH:12])[OH:11]>O>[CH3:9][O:8][C:1]1[CH:7]=[C:6]([S:10]([OH:13])(=[O:12])=[O:11])[CH:5]=[CH:4][C:2]=1[OH:3]
Reactant: O=S(=O)(O)O
Reactant: COc1ccccc1O
Solvent: O
Product: COc1cc(S(=O)(=O)O)ccc1O

Procedure:
A solution of guaiacolsulfonic acid in sulfuric acid was prepared. Water in the recirculating water bath was heated to 65 degrees Centigrade. The weight of available stock guaiacol, purified reagent, that contained 1.63 moles of guaiacol was calculated. The amount of available stock of sulfuric acid NF that contained 3.41 moles of sulfuric acid was calculated. A 1 liter Corning Pyrix bottle No. 1395 was placed on the Mettler PG-5002-S balance. A 600 mL beaker was filled with approximately 400 mL guaiacol, purified reagent from the available stock bottle. A quantity of 1.63 moles of guaiacol as guaiacol, purified reagent by weight from the beaker was added to the bottle.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[CH2:23][CH2:24][NH2:25]>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:24][CH2:23][C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[CH3:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: Cc1ccccc1CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Product: Cc1ccccc1CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Yield: 64.4 %

Procedure:
Using a method similar to Example 405, using 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.0294 g, 0.113 mmol) and 2-methylphenethylamine (0.017 g, 0.124 mmol) gives the title compound (0.0276 g, 65.2%): TOF MS ES+ 380.2 (M+H)+, HRMS calcd for C22H23N3O2F 380.1774 (M+H)+, found 380.1741, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=8.2 min. 100% purity.
Reaction SMILES: C([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[O:23]([C:21]1[CH:22]=[C:17]([N:14]2[CH2:15][CH2:16][C:12]3([NH:8][CH2:9][CH2:10][CH2:11]3)[CH2:13]2)[CH:18]=[N:19][CH:20]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCCC23CCN(c2cncc(Oc4ccccc4)c2)C3)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: c1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1
Yield: 92.7 %

Procedure:
To a solution of 1-benzyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (690 mg, 1.79 mmol) in ethanol (25 mL) in a pressure bottle was added concentrated HCl (1 mL) and Pearlman's catalyst (Pd(OH)2, 20% on carbon, 50 mg). The solution was shaken under 50 psi of hydrogen gas for 8 h. The catalysts was removed by filtration through Celite, and the filter cake was washed with ethanol (20 mL). The solvent was removed by rotary evaporation, and the residue was basified with saturated aqueous sodium bicarbonate to pH 8-9. Solid sodium chloride (2 g) was added, and the solution was extracted with chloroform (4×20 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford 490 mg of the desired compound as a light brown viscous liquid (92.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][S:11][N:10]=2)[CH:5]=[C:6]([SH:8])[CH:7]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([Cl:19])=[O:16])=[CH:12][S:11][N:10]=2)[CH:5]=[C:6]([SH:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1csnc1-c1cc(S)cc(Cl)c1
Product: O=C(Cl)c1csnc1-c1cc(S)cc(Cl)c1
Reaction time: 20 h

Procedure:
50 g of the product of step (b) are dissolved in 500 ml of thionyl chloride and the mixture is held at 50° for 20 hours. The thionyl chloride is removed at 12 mm to obtain the heading compound.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1cccc(Cl)c1
Product: O=C(Nc1cccc(Cl)c1)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-chloroaniline as the starting materials.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[NH:15][C:16]([C:26](F)(F)F)=[N:17][C:18]=3[C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:8]=2[N:7]([CH3:30])[C:6]1=[O:31])[CH:2]([CH3:4])[CH3:3].[OH-].[NH4+:33]>>[CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[NH:15][C:16]([C:26]#[N:33])=[N:17][C:18]=3[C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:13][C:8]=2[N:7]([CH3:30])[C:6]1=[O:31])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc3c(c2)n(C)c(=O)n3CC(C)C)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cccc(-c2nc(C#N)[nH]c2-c2ccc3c(c2)n(C)c(=O)n3CC(C)C)c1
Reaction time: 120 h

Procedure:
1-Isobutyl-3-methyl-5-(5-m-tolyl-2-trifluoromethyl-3H-imidazol-4-yl)-1,3-dihydro-benzoimidazol-2-one (prepared as described previously using the method described for example 63 and Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1974, 17(11), 1182–1188, 20 mg, 0.05 mmol) was suspended in 5% aqueous ammonium hydroxide solution (4.7 mL). The suspension was stirred for 5 days, after which time the reaction was concentrated in vacuo. The resulting material was purified by LC (Waters Symmetry C8, acetonitrile/water 40% to 100%) to afford 8 mg of the title compound as a white solid. MS (M+1)=386.2
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([S:13]([CH3:15])=O)[O:7]2.[OH:17][C:18]1[CH:23]=[CH:22]C(S)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([S:13][C:15]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[O:7]2
Reactant: Oc1ccc(S)cc1
Reactant: CS(=O)c1cc(=O)c2c(O)cc(O)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1cc(Sc2ccc(O)cc2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 32 mg of 5,7-dihydroxy-2-methylsulfinylchromone (0.134 mmol), 20 mg of 4-hydroxybenzenethiol (0.161 mmol), 41 mg of potassium carbonate (0. 295 mmol) and 2 ml acetone was stirred overnight at room temperature. The reaction solution was neutralized with dilute hydrochloric acid and then extracted twice with ethyl acetate. The organic layer was washed with saturated NaCl water and dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was subjected to recrystallization from acetone-hexane, to give 14.6 mg of 5,7-dihydroxy-2-(4-hydroxyphenylthio)chromone (36% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:12]1[C:16]([N:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)C(=O)OC(C)(C)C)=[CH:15][N:14]=[N:13]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:9]([C:5]1[CH:4]=[C:3]([N:12]2[C:16]([NH:17][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[CH:30][CH:31]=3)=[CH:15][N:14]=[N:13]2)[C:2]([OH:1])=[CH:7][C:6]=1[OH:8])([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(-n2nncc2N(Cc2ccc(N3CCOCC3)cc2)C(=O)OC(C)(C)C)c(O)cc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(-n2nncc2NCc2ccc(N3CCOCC3)cc2)c(O)cc1O
Yield: 50 %

Procedure:
A solution of the intermediate from Step D in DCM/TFA (1/1, 5 ml) was stirred for 12 hours at RT. The reaction mixture was concentrated under reduced pressure and the crude reaction mixture was purified by column chromatography (DCM/MeOH: 95/5). The title compound was obtained as slightly brown solid.
Reaction SMILES: C(Cl)CCl.[OH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH:31]=[O:32])[CH2:19][CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([O:5][CH2:6][C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[O:27])=[CH:24][C:23]=2[CH:31]=[O:32])[CH2:19][CH2:18]1
Reactant: O=Cc1cc(C(=O)O)ccc1OCC1CC1
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=Cc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (2.52 g, 13.16 mmol) was added to a solution of compound benzyl 2-hydroxyacetate (2.02 g, 12.15 mmol), 4-(cyclopropylmethoxy)-3-formylbenzoic acid (2.23 g, 10.13 mmol), and DMAP (247 mg, 2.03 mmol) in DCM (20 ml) at RT under nitrogen atmosphere. The mixture was stirred at RT overnight. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-formylbenzoate was obtained (3.73 g, quantitative yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][NH2:6].[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:30])[CH2:15][CH2:16][C@@H:17]2[CH2:27][CH:28]=O)[CH2:9]1>[OH-].[Na+].O1CCOCC1>[NH2:2][CH2:3][CH2:4][O:5][N:6]=[CH:28][CH2:27][C@H:17]1[CH2:16][CH2:15][C@:14]2([OH:30])[C@H:13]3[C@H:22]([CH2:21][CH2:20][C@:18]12[CH3:19])[C@:23]1([CH3:26])[C@@H:10]([CH2:9][C@@H:8]([OH:7])[CH2:25][CH2:24]1)[CH2:11][CH2:12]3
Reactant: NCCON
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC=O)CC[C@]12O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](CC=NOCCN)CC[C@]12O
Yield: 52.7 %

Procedure:
To a solution of 0.47 g of 2-aminoethoxyamine hydrochloride in 16 ml of 1N NaOH and 20 ml of dioxane a solution of 0.89 g of 3β,14β-dihydroxy-5β-androstane-17β-ylacetaldehyde (Prepn. 2) in 15 ml of dioxane was added at room temperature. After 20 hrs the solution was extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography (SiO2) using chloroform with increasing amounts of methanol (6 to 20%) as the eluant. The fractions containing the title compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether to give 0.55 g of the title compound (I-bf), as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[CH:22]1([C:25](C(Cl)=O)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26]
Reactant: O=C(Cl)C(=O)C1CC1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: c1ccncc1
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)C1CC1
Temperature: 80 °C
Yield: 81.4 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.2 g, 0.71 mmol) in pyridine (2 mL), 0.071 mL (0.78 mmol) of cyclopropanoylcarbonyl chloride were added. The mixture was heated at 80° C. for 4 h and the solvent was evaporated. The crude mixture was extracted between ethyl acetate and water, the organic layer was dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (90:10 dichloromethane/methanol) to give the title compound (0.202 g, 82% of yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29].C([O-])([O-])=O.[K+].[K+]>>[CH3:27][S:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:20])[F:21])=[CH:11][C:10]([C:23]([F:25])([F:24])[F:26])=[N:9]3)=[CH:6][CH:7]=2)[CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29]
Reactant: FC(F)(F)c1cc(-c2ccccc2C(F)(F)F)n(-c2ccc(Br)cc2)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3nc(C(F)(F)F)cc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
A mixture of 1-(4-bromophenyl)-3-trifluoromethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrazole (135 mg, 0.31 mmol), 3-methanesulfonyl-phenylboronic acid (74 mg, 0.37 mmol), K2CO3 (0.13 g, 0.93 mmol), Cl2Pd(dppf).DCM (24 mg, 10 mol %) and H2O (0.2 mL) in dioxane (2 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 16 h the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 0:100 to 40:60) to give the title compound (121 mg, 76%). 1H NMR (DMSO-d6): δ 8.15 (m, 1H), 8.03 (d, 1H), 7.91 (m, 2H), 7.83 (d, 2H), 7.71-7.76 (m, 3H), 7.66 (m, 1H), 7.40 (d, 2H), 7.18 (s, 1H); MS(ES): 511 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:17].O>O1CCCC1>[CH3:17][O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
Sodium hydride (2.2 g, 80% dispersion in mineral oil, 73.2 mmol) was added to an ice-cooled solution of (3S)-N-tert-butoxycarbonylpyrrolidin-3-ol (U.S. Pat. No. 6,180,627 preparation 78), (12.5 g, 66.7 mmol) in tetrahydrofuran (330 ml), and the solution was stirred at room temperature for an hour. Iodomethane (14.5 g, 100 mmol) was then added and the reaction stirred for 18 hours. Water (100 ml) was added and the mixture concentrated under reduced pressure to remove the organic solvents. The solution was partitioned between water (750 ml) and ethyl acetate (750 ml) the layers separated, and the organic solution dried over magnesium sulphate and evaporated under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([CH:4]([CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C(CCCc1ccccc1)C(=O)NC(C)c1nnc(Cc2cccc3ccccc23)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)C(CCCc1ccccc1)c1nc(C)c2c(=O)[nH]c(Cc3cccc4ccccc34)nn12

Procedure:
Analogously to Example 1, 80 mg (0.17 mmol) of 2-acetyl-N-{1-[3-(1-naphthylmethyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}-5-phenylpentanamide and 28.0 mg (0.18 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-4-phenylbutyl)-5-methyl-2-(1-naphthylmethyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[OH:9][CH2:10][C:11]([CH3:15])([CH2:13]O)[CH3:12].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH3:12][C:11]1([CH3:15])[CH2:10][O:9][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:13]1
Reactant: O=C1CCC(=O)CC1
Reactant: CC(C)(CO)CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)COC2(CCC(=O)CC2)OC1

Procedure:
1,4 cyclohexane dione (25.0 grams) and neopentyl glycol (23.5 grams) were dissolved in chloroform (200 ml). Then sulfuric acid (4.0 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10–20° C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. Hexane (250 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0–5° C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal.
Reaction SMILES: Cl.[NH2:2]O.C([O-])(=O)C.[Na+].[Cl:9][C:10]1[C:11]([N:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:12]([C:17](=[O:28])[C:18](=[CH:24]OCC)[C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH:13]=[CH:14][C:15]=1[Cl:16].O>C(O)C>[Cl:9][C:10]1[C:11]([N:29]([CH2:34][CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:12]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:17]([C:18]1[CH:24]=[N:2][O:20][C:19]=1[CH:21]1[CH2:23][CH2:22]1)=[O:28]
Reactant: CCOC=C(C(=O)c1ccc(Cl)c(Cl)c1N(CC)C(=O)OC)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(C(=O)OC)c1c(C(=O)c2cnoc2C2CC2)ccc(Cl)c1Cl
Yield: 40.9 %

Procedure:
Hydroxylamine hydrochloride (0.53 g) and sodium acetate (0.63 g) were added to a stirred solution of 1-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)phenyl]-3-cyclopropyl-2-ethoxymethylenepropane-1,3-dione (2.88 g) in ethanol. After 05 hours water was added, and the mixture extracted (dichloromethane), dried (magnesium sulphate) and evaporated to dryness. Purification by chromatography gave 4-[3,4-dichloro-2-(N-ethyl-N-methoxycarbonylamino)benzoyl]-5-cyclopropylisoxazole (compound number 2, 1.09 g), m.p. 76-78° C. as a white solid.
Reaction SMILES: C1([C@H]2[O:17][C:16](=[O:18])[C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:9]3[C@H]2C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCO.[Pd](Cl)Cl>[NH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:16]([OH:18])=[O:17]
Reactant: O=C1O[C@H](c2ccccc2)[C@H](c2ccccc2)N2CCCCC[C@@H]12
Agent: Cl[Pd]Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCCCN1
Reaction time: 12 h

Procedure:
Palladium (II) chloride (800 mg, 4.51 mmol) is added to a solution of (3R,4S,9aS)-3,4-diphenyl-octahydro-2-oxa-4a-aza-benzocyclohepten-1-one (4.5 g, 14.0 mmol) in THF (140 mL) and EtOH (160 mL). The reaction mixture is stirred for 12 hours under H2 atmosphere at 50 psi, then filtered through celite that is washed with EtOH. Removal of the solvent under reduced pressure affords the title compound m/z 144 [M+H].
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[K+].[Br-].C[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:1]([O:4][CH2:5][C:2]1[C:1](=[O:3])[O:4][C:5]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:6]=2)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCCCCC
Agent: [Br-]
Agent: [K+]
Product: CCOCc1cc2ccccc2oc1=O

Procedure:
(0.15 g, 73%); m.p.: 95-96° C., Rf=0.38 (ethyl acetate:n-Hexane=1:5); IR (KBr cm−1): 2970, 2924, 2863, 2341, 1717, 1605, 1574, 1447, 1384, 1283, 1172, 1116, 1061, 919, 756, 630; 1H-NMR (400 MHz, CDCl3) δ/ppm: 1.31 (3H, t, J=7.0 Hz, OCH2CH3), 3.68 (2H, q, J=7.0 Hz, OCH2CH3), 4.46 (2H, d, J=1.6 Hz, CH2OCH2CH3), 7.28 (1H, td, J=7.6, 1.2 Hz, ArH), 7.34 (1H, d, J=8.0 Hz, ArH), 7.48-7.52 (2H, ArH), 7.81 (1H, t, J=1.6 Hz, H-4); 13C-NMR (100 MHz, CDCl3) δ/ppm: 15.2, 66.9, 66.9, 116.5, 119.2, 124.4, 126.4, 127.7, 131.0, 138.1, 153.1, 160.5; MS (EI) m/z: 175 ([M-(C2H5)]+, 53%), 160 (100%), 132 (51%), 131 (42%); Anal. calcd for C12H12O3 (204.22): C, 70.57; H, 5.92. found: C, 70.60; H, 5.95.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)[N:13]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.19 ml of 4-trifluoromethyl-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 146 mg of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 60 %

Procedure:
(S)-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DIEA (0.99 mL, 5.7 mmol) were placed in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.55 g, 60% yield).