Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C:12]1([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: COc1ccc(S(=O)(=O)NC2(C(=O)NOCc3ccccc3)CCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)NC2(C(=O)NO)CCCC2)cc1
Reaction time: 3.5 h

Procedure:
A solution of 1-(4methoxybenzenesulfonylamino)cyclopentane-1-carboxylic acid benzyloxyamide (1.50 grams, 3.71 mmole) in methanol (200 mL) was treated with 5% palladium on barium sulfate (0.75 grams) and hydrogenated at 3 atmospheres pressure for 3.5 hours in a Parr shaker. The catalyst was removed by passage through a 0.45 μm nylon filter and the filtrate was concentrated to afford 1-(4-methoxybenzenesulfonylamino)-cyclopentane-1-carboxylic acid hydroxyamide as a white solid, 1.13 grams (97%). MS: 313 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]1[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:37][CH2:38][O:39][CH3:40]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:37][CH2:38][O:39][CH3:40])[CH2:10][CH:9]1[C:14]1[N:15]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1c1nc(-c2ccc(Br)cc2)cn1COCC[Si](C)(C)C
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC1CC(c2nc(-c3ccc(Br)cc3)cn2COCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (222 mg) was dissolved in DMF (4 mL), and NaH (25 mg) was added. The mixture was stirred over 20 min. and 1-bromo-2-methoxy-ethane was added slowly, and then stirred for 2.5 hours. The mixture was quenched with 3 mL of sat. NH4Cl and was taken up in ethyl acetate (50 mL). The organic phase was washed with saturated sodium bicarbonate (1×50 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 20-60% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 2-[4-(4-Bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (209 mg, 85%) as a clear oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[Cl:33][C:34]1[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[C:35]=1[S:41](Cl)(=[O:43])=[O:42]>>[Cl:33][C:34]1[N:38]([CH3:39])[N:37]=[C:36]([CH3:40])[C:35]=1[S:41]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:30])([F:29])[F:31])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32])(=[O:42])=[O:43]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
5-Chloro-N-{2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-1,3-dimethyl-1H-pyrazole-4-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride following General Procedure U.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C]=O.[BH4-].[Na+].Cl.[C:18](=O)(O)[O-:19].[Na+]>CO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C.C(N(CC)CC)C>[OH:19][CH2:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(Br)ccnc2c1
Reactant: O=C([O-])O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: OCc1ccnc2cc(Cl)ccc12
Temperature: 120 °C
Yield: 68 %

Procedure:
A 200 ml stainless steel autoclave was loaded with 4-bromo-7-chloroquinoline (1.2 g, 5.0 mmol) (Can. Pat. CA 94-2133620 941004), bis(triphenylphosphine)palladium chloride (0.1 g), triethylamine (3 ml) and ethanol (40 ml) and pressurized to 200 psi with carbon monoxide. The autoclave was heated at 120° C. for 12 hours, cooled, and vented. Solids were removed by filtration through celite and the mother liquor concentrated in vacuo. The residue was taken up in chloroform (50 ml), washed with water (3×50 ml), saturated brine (50 ml), and dried (Na2SO4). Filtration and removal of solvent left 1.3 g of a brown liquid. Flash chromatography on silica using 1 vol % CH3CN in CH2Cl2 as eluent afforded product as a colorless syrup which solidified to a waxy solid. This solid was dissolved in methanol (50 ml) and sodium borohydride was added over two hours until judged complete by TLC. The reaction was diluted with water and acidified with 1N hydrochloric acid and then neutralized with sodium bicarbonate. The resulting solid was recovered via filtration, dissolved in ethyl acetate and dried (MgSO4). Filtration and concentration afforded the desired compound (mp: 160° C., 0.66 g, 68% over two steps).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCN(CCOC)c1ccc([N+](=O)[O-])cc1

Procedure:
1-fluoro-4-nitrobenzene (133 mg, 0.94 mmol), bis(2-methoxyethyl)amine (125 mg, 0.94 mmol) and potassium carbonate (143 mg, 1.04 mmol) were stirred in DMSO (2 mL) at 70° C. for 24 hours. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound. MS (ESI+) m/e 255.1 (M+H)+.
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].O.[CH3:13][C:14]1C=CC(S(O)(=O)=O)=C[CH:15]=1>COC(OC)(C)C>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:15])([CH3:13])[O:1]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Solvent: COC(C)(C)OC
Solvent: O
Product: CON(C)C(=O)[C@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 581.6 %

Procedure:
(S)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol, 4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica plug (1.5 L, eluting with 25% EtOAc in hexanes) to afford (S)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (23.1 g, 114 mmol, 58.0% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:20]4[CH2:29][CH2:28][C:23]5(OCC[O:24]5)[CH2:22][CH2:21]4)[N:18]=[CH:19][C:14]3=[C:13]([N:30]3[CH2:36][CH:35]4[O:37][CH:32]([CH2:33][CH2:34]4)[CH2:31]3)[N:12]=2)=[CH:7][CH:6]=1>Cl>[CH3:1][O:2][C:3](=[O:38])[NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:20]4[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH2:21]4)[N:18]=[CH:19][C:14]3=[C:13]([N:30]3[CH2:36][CH:35]4[O:37][CH:32]([CH2:33][CH2:34]4)[CH2:31]3)[N:12]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC5(CC4)OCCO5)c3n2)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Methyl{4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate (0.2 g, 0.38 mmol) was dissolved in conc. HCl (2.0 mL) and stirred at room temperature for 1 hr. The reaction was cooled in an ice bath and basified with 10N. sodium hydroxide to precipitate a white solid. The solid was filtered and washed with water and purified by Gilson HPLC to give the desired product (93 mg) MS m/z=477 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C.[F:30][B-](F)(F)F.C(N([S+](F)F)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([F:30])[CH2:11][O:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: F[B-](F)(F)F
Reactant: OC1(c2ccc(Br)cn2)COC1
Agent: CCN(CC)[S+](F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC1(c2ccc(Br)cn2)COC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of the product of Step 1, Example 8 (300.0 mg, 1.30 mmol) in methylene chloride (3.00 mL) is added to a mixture of triethylamine trishydrofluoride (0.531 mL, 3.26 mmol), triethylamine (0.273 mL, 1.96 mmol), and (Diethylamino)difluorosulfonium tetrafluoroborate (597 mg, 2.61 mmol) in methylene chloride (20.0 mL) at −78° C. The reaction mixture is slowly allowed to warm to 0° C. More (Diethylamino)difluorosulfonium tetrafluoroborate (100.0 mg, 0.437 mmol) is added and stirring continued at this temperature for 1 hour. The mixture is diluted with methylene chloride, washed with saturated sodium hydrogen carbonate solution, brine, dried over magnesium sulfate, and then concentrated. The residue is purified by chromatography on silica gel eluting with a gradient of 0-30% ethyl acetate to afford the title compound (200 mg): MS (ESI+) m/z 232.1/234.1 [M+H].
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27].CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:31][CH2:30][CH2:29][C@H:25]5[C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC[C@H]3C(N)=O)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and L-prolinamide, were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from methanol to give 338 as a white solid (115 mg, 44%). LCMS: RT=2.48 min, [M+H]+ 409. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1H, s), 7.88 (1H, s), 7.83 (1H, s), 7.33 (1H, br), 6.92 (1H, br), 5.97-5.96 (1H, m), 5.94 (1H, s), 4.53-4.45 (4H, m), 4.30 (1H, d, J=8.51 Hz), 3.59 (1H, s), 3.37 (1H, d, J=9.93 Hz), 2.18 (1H, m), 1.95 (3H, m), 1.47 (6H, dd, J=6.59, 3.43 Hz)
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:33][CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(S(C)(=O)=O)cc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 92.4 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-ethoxy-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (52 mg, 0.076 mmol) and 1.0 N aqueous sodium hydroxide (1.0 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethoxy-4′-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (44 mg, 91%) as a light brown solid: ES(+)-HRMS m/e calcd for C34H42O9S (M+Na)+ 649.2442. found 649.2442.
Reaction SMILES: [C:1]1([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH:19]([CH3:31])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[Cl:30])=O>CO>[Cl:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[C:20]1[N:14]=[C:12]([N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:19]=1[CH3:31]
Reactant: CCCN(C(N)=S)c1cccc2ccccc12
Reactant: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Solvent: CO
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cccc2ccccc12
Yield: 73.5 %

Procedure:
A solution containing 0.5 g of N-naphth-1-yl-N-propylthiourea and 0.5 g of 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one in 15 ml of methanol is heated at reflux for 6 hours. The reaction mixture is then evaporated to dryness and then, successively, the residue is taken up in water, basified with 33% sodium hydroxide and extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and concentrated under vacuum. The residue is then purified on a column of silica gel eluted with ethyl acetate, to provide 0.56 g of a yellow oil. 1H NMR (CDCl3): 0.97 (t, J=7.7, 3H, --CH2 --CH3), 1.73 (sex, 2H, --CH2 --CH3), 2.04 (s, 3H, --CH3), 3.82 (s, 3H, --OCH3), 3.90 (m, 2H, --CH2 --CH2 --CH3), 6.89 (dd, J=1.8, J=8.0, 1H, H5arom) 7.02 (d, J=1.8, 1H, H3arom), 7.50-7.70 (m, 4H, H2, H3, H8 and H6arom), 7.85-8.10 (m, H, H6, H7, H4 and H5).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)=[N:8]2)[NH2:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:51]1[CH:56]=[CH:55][CH:54]=[N:53][C:52]=1[C:57](O)=O.CCN(C(C)C)C(C)C.C(O)(=O)C>C(OCC)(=O)C.CN(C=O)C>[C:31]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:8][C:9]3[CH:10]=[CH:11][N:12]4[C:57]([C:52]5[N:53]=[CH:54][CH:55]=[CH:56][N:51]=5)=[N:2][N:1]=[C:3]4[C:4]=3[CH:5]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(O)c1ncccn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) (267 mg, 0.554 mmol), EDC (138 mg, 0.721 mmol), HOBt (97 mg, 0.721 mmol), pyrimidine-2-carboxylic acid (89 mg, 0.721 mmol), DIPEA (0.367 mL, 2.218 mmol), and DMF (3 mL). The reaction mixture was then capped & heated under microwave irradiation at 100° C. for 5 minutes. The mixture was cooled, acetic acid (0.476 mL, 8.32 mmol) was added and the reaction was then capped & heated under microwave irradiation at 80° C. for 5 minutes. The reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 0-10% IPA/DCM. The appropriate fractions were combined and the solvent was removed in vacuo to give tert-butyl {1-[4-(9-phenyl-3-pyrimidin-2-yl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (1-6d) as an orange solid. MS (M+H)+: observed=570.2, calculated=570.7.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:25]=[C:24](N)[CH:23]=[N:22][C:9]=3[N:10]=[C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[BrH:37]>O>[N:1]1([C:7]2[C:8]3[CH:25]=[C:24]([Br:37])[CH:23]=[N:22][C:9]=3[N:10]=[C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Br
Reactant: Nc1cnc2nc(OCCN3CCOCC3)nc(N3CCOCC3)c2c1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Brc1cnc2nc(OCCN3CCOCC3)nc(N3CCOCC3)c2c1
Temperature: 60 °C

Procedure:
4-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-amino-pyrido[2,3-d]pyrimidine (1.45 g; 4 mmol) and cuprous bromide (1.15 g; 8 mmol) was dissolved in a mixture of water (25 mL) and concentrated hydrobromic acid (25 mL). The solution was chilled in an ice bath, and to it was added sodium nitrite (340 mg; 5 mmol, in aqueous solution). The solution was stirred for ten minutes, and then heated to 60° C. for one hour. It was then poured into a 10% solution of potassium carbonate, and extracted with dichloromethane (2×50 mL). The organic layer was dried over magnesium sulfate, evaporated, and the product was purified by column chromatography to give 4-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-bromo-pyrido[2,3-d]pyrimidine (0.98 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(C)=O)C(=O)O
Temperature: 4 °C

Procedure:
A mixture of ethyl 2-methoxyimino-3-oxo-butyrate, syn isomer (52 g), ethanol (300 cc) and 1 N sodium hydroxide solution (330 cc) is heated under reflux for 15 hours. The mixture is concentrated by evaporation of ethanol at 20° C. under a pressure of 20 mm Hg (2.7 kPa) and is then extracted with methylene chloride (150 cc). The aqueous phase is treated with animal charcoal (1 g), filtered, saturated with sodium chloride, cooled to 4° C. and acidified to pH2 with 2 N hydrochloric acid in the presence of methylene chloride (200 cc). It is then re-extracted with the same solvent (2×100 cc), followed by ethyl acetate (6×200 cc). The organic phases are dried over sodium sulphate and concentrated to dryness separately at 20° C. under 20 mm Hg (2.7 kPa). The residues are combined and treated with isopropyl ether (80 cc) for 4 hours, with very vigorous stirring. The crystals obtained are filtered off and dried, and 2-methoxyimino-3-oxo-butyric acid, syn isomer (8.9 g) is thus obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH:32]([CH3:34])[CH3:33])[CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: O=C(O)Cc1cc[nH]c1
Product: COc1ccc(N2CCN(C(=O)Cc3cc[nH]c3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using (1H-pyrrol-3-yl)-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil. LC/MS (Method B) 2.75 min, [M+1]+ 448. Potency class A.
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[C:7]2[CH2:8][NH:9][CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5].[OH-].[Li+].Cl>CO.C1COCC1.O>[CH2:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=2[CH2:8][NH:9]1
Reactant: COC(=O)c1cccc2c1CNC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc2c1CNC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 4.4 %

Procedure:
To a suspension of the 2,3-dihydro-1H-isoindole-4-carboxylic acid methyl ester hydrochloride salt (0.18 g, 0.83 mmol) in 25% MeOH/THF (4 ml) was added dropwise lithium hydroxide (0.08 g, 3.32 mmol) in water (1 ml), followed by addition of water (2 ml) and the clear solution stirred at room temperature under nitrogen for 5 h. The solution was acidified with aq. HCl. and purified by ion-exchange (DOWEX™ 50WX2-100) resin eluting with a solvent gradient of ammonia:water (5:95) to give the title compound (0.0059 g, 4%) as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C@H:9]([S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[C@@H:8]([CH2:17][OH:18])[C:7]1=[O:19].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C>[OH:18][CH2:17][C@@H:8]1[C@@H:9]([S:10]([C:13]([CH3:15])([CH3:14])[CH3:16])(=[O:12])=[O:11])[NH:6][C:7]1=[O:19]
Reactant: COc1ccc(CN2C(=O)[C@H](CO)[C@H]2S(=O)(=O)C(C)(C)C)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)S(=O)(=O)[C@H]1NC(=O)[C@@H]1CO

Procedure:
A solution of 74 mg (0.2 mmol) of 1-(2,4-dimethoxybenzyl)-3-(S)-hydroxymethyl-4-(R)-tert.butylsulphonyl-2-azetidinone (see Example 20), 486 mg (1.8 mmol) of potassium peroxydisulphate and 174 mg (1.0 mmol) of dipotassium hydrogen phosphate in 4 ml of acetonitrile is stirred for 2 hours at 65° under a reflux condenser, the resulting reaction mixture is freed from acetonitrile under reduced pressure and the aqueous residue is extracted with ethyl acetate. After drying of the organic phase over Na2SO4 and concentration by evaporation in vacuo, a residue is obtained from which the title compound is obtained in the form of colourless crystals by adding a little methylene chloride and ether.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:17].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CN(C)C(=O)C>[F:17][C:3]1[CH:4]=[C:5]([S:8]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(CCC(F)(F)F)c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(CCC(F)(F)F)c1ccc(N2CCNCC2)c(F)c1
Temperature: 80 °C

Procedure:
To 0.5 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzene in 5 ml N,N-dimethylacetamide was added 1.5 mmol piperazine, and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: methanol/dichloromethane gradient) to afford the title compound. MS (m/e): 341.2 (M+H+, 100%)