Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1([CH2:34][C:35](Cl)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[CH:29]1([CH2:34][C:35]([NH:19][C:15]2[CH:14]=[C:13]([N:10]3[CH:11]=[N:12][C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:9]3)[CH:18]=[CH:17][N:16]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1CCCC1)Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(3-Phenylamino-[1,2,4]triazol-1-yl)-pyridin-2-ylamine (50 mg, 0.20 mMol) was dissolved in 2.5 mL of NMP with (50 μL, 67.4 mg, 0.52 mMol) of Hunig's base and (30 μL, 32 mg, 0.2 mMol) of cyclopentylmethyl carbonyl chloride. The reaction was stirred at ambient temperature for 18 hr. LC shows starting material, mono acylated material, and a majority of the bis acylated imide. Another alliquot of the acylating agent was added and the reaction was stirred until all starting material was consumed. Five drops of 2.0N sodium hydroxide was then added and the reaction was stirred for ten hours at ambient temperature, until all of the imide was hydrolyzed. The reaction mixture was acidified with TFA and the crude material was purified via HPLC, C18 silica with a gradient of acetonitrile/water/0.1% TFA as the eluent. Yield˜13 mg of a pale yellow powder as the TFA salt; (18%). 1H NMR 500 MHz (DMSO-d6) ∂ 1.29m, 2H), 1.5(m, 2H), 1.77(m, 2H), 2.25(m, 1H), 2.4(d, 2H), 6.88(t, 1H), 7.28(t, 2H), 7.53(d, 1H), 7.63(d, 2H), 8.35(d, 1H), 8.55(d, 1H), 9.2(s, 1H), 9.57(s, 1H), 10.6(s ex, 1H). LC/MS [M+H+] 363
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=2)[NH:6]1)=[O:4].[C:19]([O:23][C:24]([NH:26][C@@H:27]([CH2:31][CH3:32])[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][C:15]([F:18])([F:16])[F:17])[CH:11]=2)[N:6]1[C:28](=[O:29])[C@@H:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH3:32])=[O:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1Cc2cc(OC(F)(F)F)ccc2N1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccc(OC(F)(F)F)cc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-trifluoromethoxyindoline-2(R/S)-carboxylic acid methyl ester (1.95 g, 7.47 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (1.52 g, 7.47 mmol) dissolved in dried dichloromethane (15 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (1.00 ml, 7.96 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown oil which was purified by column chromatography on silica gel first by using 95:5 dichloromethane: diethyl ether as eluent, then another column on silica gel by using 7:3 petroleum spirit: diethyl ether. A yellow foam was obtained which was the mixture of two diastereomers.
Reaction SMILES: [C:1]([N:4]1[CH2:27][CH:26]([OH:28])[CH2:25][C@H:5]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=2)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)=[O:7])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CO>[C:1]([N:4]1[CH2:27][CH:26]([O:28][C:35](=[O:37])[CH3:36])[CH2:25][C@H:5]1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=2)[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(O)C[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)OC1C[C@@H](C(=O)Nc2ccc(-c3ccc(C(=O)O)c(=O)[nH]3)cc2)N(C(C)=O)C1

Procedure:
A solution of 29.9 g (0.078 mol) of the above pyridone acid, 120 ml of pyridine, and 60 ml of acetic anhydride is stirred overnight at room temperature. The solution is cooled and upon adding methanol, a precipitate forms. The mixture is cooled and then filtered and the solid is air dried. The solid is recrystallized from 1800 ml of 20% water in methanol and dried at 50° under vacuum to give 21.1 g of 6-[4-[N-acetyl-4-(acetyloxy)-L-prolylamino]phenyl]-1,2-dihydro-2-oxonicotinic acid; [α]D23 +17.3° (cl, 75% DMF/pyridine).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCC2CC2)cc1Cl
Temperature: 50 °C
Yield: 80.2 %

Procedure:
A solution of 2-chloro-4-hydroxybenzaldehyde (1.00 g, 6.39 mmol), bromomethylcyclopropane (0.93 mL, 9.58 mmol) and potassium carbonate (1.77 g, 12.8 mmol) in DMF (8 mL) was stirred under heating at 50° C. for 1 day. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:1) to give the title compound (1.08 g, yield 80%) as an oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]([OH:29])=[O:28])[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:26][C:27]([OH:29])=[O:28])[C:16]3[S:20][N:19]=[C:18]([N:21]4[CH:25]=[CH:24][N:23]=[CH:22]4)[N:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCCN(CC(=O)O)c1nc(-n2ccnc2)ns1)Cc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
[[3-(Benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid (70 mg, 140 μmol) was dissolved in TFA/DCM (1:1, 2 mL) and stirred at room temperature for 30 min. SiO2 (3 g) was added and the solvent was evaporated to afford a white slurry. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 58 mg (99%) of [{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid as a white solid. [M+H]+ 416.92; 1H NMR (400 MHz, d6-DMSO) δ 9.05 (s, 1H), 8.79 (br s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.06 (s, 1H), 6.97 (m, 2H), 6.06 (s, 2H), 4.39 (br s, 2H), 4.26 (s, 2H), 3.66 (m, 2H), 3.00 (m, 2H), 2.01 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:4]=[C:3]([CH2:2][C:20]#[N:21])[CH:7]=[N:6]1
Reactant: [C-]#N
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole, prepared as in EP 350 237, was treated with potassium cyanide in dimethyl sulphoxide at room temperature for two hours. The mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-ylacetonitrile. In a similar manner to Example 6, this compound was converted to 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole,. (Compound 29a).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[O:18][CH:19]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O1CCCC1>CO>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3[N:16]=[C:17]([CH2:20][CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[O:18][CH:19]=3)=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C(=C/c1cccs1)\c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Solvent: CO
Solvent: C1CCOC1
Product: c1csc(CCc2nc(COc3ccc(CCCn4ccnc4)cc3)co2)c1

Procedure:
A solution of 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-(2-thienyl)ethenyl]oxazole (200 mg) in methanol (10 ml)-tetrahydrofuran (4 ml) was hydrogenated on palladium carbon (10%, wet, 70 mg) at 4 atm. After removal of the catalyst by filtration, the filtrate was concentrated. The hydrogenation was repeated three times to obtain 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-[2-(2-thienyl)ethyl]oxazole. Recrystallization from ethyl acetate-methanol gave colorless prisms (155 mg, 79%), mp 68-70° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:19]([CH2:18][CH2:17][CH2:16][Cl:15])(=[O:21])=[O:20]
Reactant: COC(CN)OC
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of aminoacetaldehyde dimethyl acetal (2.22 mL, 20.4 mmol) and triethylamine (3.54 mL, 25.4 mmol) in dichloromethane (60 mL) was added 3-chloropropanesulfonyl chloride (2.06 mL, 16.9 mmol) in dichloromethane (40 mL) dropwise. The reaction mixture was warmed to room temperature and stirred one hour. The reaction mixture was quenched with water. The organic phase was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by trituration with ether provided N-[2,2-bis(methyloxy)ethyl]-3-chloro-1-propanesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.56 (s, 1 H), 4.42 (t, J=5.0 Hz, 1 H), 3.68 (t, J=6.1 Hz, 2 H), 3.42 (s, 6 H), 3.25-3.21 (m, 4 H), 2.28 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH:17]=[CH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.C(O)(=O)C>[Pd].C(O)C>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][CH2:18][C:19]4[CH:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:39][CH:40]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A suspension of diethyl N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)vinyl)benzoyl)-L-glutamate (0.16 g, 0.29 mmol) and 10% palladium on carbon (0.10 g) in ethanol (100 ml) was shaken under hydrogen (40 psi) overnight. Ethanol (80 ml) and acetic acid (20 ml) were added and the mixture was hydrogenated (40 psi) for 1 day. The solution was filtered, concentrated in vacuo, and the residue and catalyst were recombined in acetic acid (40 ml) and hydrogenated over the weekend. The solution was filtered, concentrated in vacuo and the product twice filtered from a small volume of methanol to give diethyl N-(4-(2-(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)ethyl)benzoyl)-L-glutamate (0.10 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, esterCH3), 1.19 (t, J=7 Hz, 3H, esterCH3), 1.90-2.18 (m, 2H, gluCH2), 2.43 (s, 3H, C3—CH3), 2.44 (t, J=7.5 Hz, 2H, gluCH2), 3.03-3.22 (m, 4H, ArCH2's), 4.04 (q, J=7 Hz, 2H, esterCH2), 4.10 (q, J=7 Hz, 2H, esterCH2), 4.37-4.47 (m, 1H, gluCH), 7.40 (d, J=8 Hz, 2H, Ar), 7.54 (dd, J=8, 1.5 Hz, 1H, Ar), 7.57 (d, J=8.5 Hz, 1H, Ar), 7.80 (d, J=8 Hz, 2H, Ar), 7.95 (d, J=8 Hz, 1H, Ar), 8.20 (d, J=9 Hz, 1H, Ar), 8.65 (d, J=7.5 Hz, 1H, gluNH), 9.72 (s, 1H, Ar), 12.51 (br s, 1H, N2H). Mass spectrum (CI-CH4): 544 (M+1, 4.2%). Anal. Calculated for C31H33N3O6.1/10H2O: C, 68.27; H, 6.14; N, 7.70. Found: C, 68.34; H, 6.10; N, 7.68.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([O:20][CH:21]1[CH2:24][CH:23]([CH2:25][OH:26])[CH2:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:1][S:2]([O:26][CH2:25][CH:23]1[CH2:24][CH:21]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(OCc2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulphonyl chloride (0.16 gm, 1.1 mmol) and triethylamine (0.26 gm, 2.6 mmol) were added to a solution of [3-(benzyloxy)cyclobutyl]methanol (0.25 gm, 1.3 mmol) (step a) in dichloromethane at 0° C. and the reaction mixture was stirred at room temperature for about 2 hours. It was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][CH:13]=[C:9]3[N:8]=[C:7]([S:14][CH3:15])[N:6]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN([CH:27]=[O:28])C>>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:27]=[O:28])=[C:9]3[N:8]=[C:7]([S:14][CH3:15])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CSc1nc(NC2CC2)n2nccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
N-Cyclopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.0 eq, 3.10 g, 14.00 mmol) was dissolved in anhydrous DMF (50 ml) under nitrogen atmosphere. Phosphorus oxychloride (5.0 eq, 6.4 ml, 69.9 mmol) was added dropwise over 5 minutes. Internal temperature rose to 45° C. The reaction was stirred in an oil bath at 70° C. for 4.5 hours. The mixture was cooled down and added dropwise into a solution of 6N NaOH (150 ml) chilled with an ice bath. The rate of addition was adjusted to maintain the internal temperature of the aqueous NaOH below 16° C. At the end of the addition, the mixture was neutralized by slow addition of 6N HCl to reach pH=5-6. The resulting solid was filtered, washed with water and dried in a vacuum oven overnight. 4-(cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde was isolated as tan solid (9.26 g, 93%). LCMS (ES): >95% pure, m/z 250 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.12 g, 62.6 mmol) in THF (80 mL) was cooled to 0° C. prior to the addition of i-PrMgCl (121.2 mmol, 60.6 mL, 2 M in THF) dropwise. The reaction was stirred for 1 h, then quenched by addition of saturated aqueous ammonium chloride (90 mL). The aqueous and organic layers were separated. The separated aqueous phase was further extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (2-18% methanol in dichloromethane) to afford the desired product (8.88 g, 84%). Rf 0.45 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.20 (m, 5H), 3.69 (s, 3H), 3.51 (s, 2H), 3.17 (s, 3H), 2.94 (d, 2H, J=11.4 Hz), 2.63-2.66 (m, 1H), 2.01 (td, J=11.7, 2.9 Hz, 2H), 1.83 (qd, J=12.8, 3.7 Hz, 2H), 1.72-1.67 (m, 2H). ESI MS found for C15H22N2O2 m/z [263.3 (M+1)].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:6].C(O)(=O)C.N([O-])=O.[Na+]>O>[CH2:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[CH:10]=[C:9]([CH2:13][CH3:14])[C:8]=1[NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 115 ml nitric acid (d=1.42) in water (900 ml) are added successively 129.9 g (0.43 moles) of N-(2,6-diethylphenyl)-p-toluenesulfonamide, glacial acetic acid (900 ml) and sodium nitrite (3.2 g). The mixture is boiled on a steam bath for 1.5 hours, then poured into ice water (2 l). The precipitate is filtered washed with water and air-dried to give crude N-(2,6-diethyl-4-nitrophenyl)-p-toluenesulfonamide.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22]>C(Cl)(Cl)Cl>[CH2:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: CCCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCN1CCN(c2ncc3c(=O)c(C(=O)OCC)cn(CC)c3n2)CC1
Yield: 84.6 %

Procedure:
As described in Example XII, the condensation of 2.8 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydropyrido(2,3-d)pyrimidine with 2.2 g of 1-propyl-piperazine, in chloroform (40 cm3) gives, after the treatments described in Example XII, 3.14 g of 2-(4'-propylpiperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine (yield 84%); melting point 149° C., after recrystallisation from ethyl acetate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:26][C:25]=1[C:35]([NH2:37])=[O:36]>C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:23][C:24]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:26][C:25]=3[C:35](=[O:36])[NH:37]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
To a stirred solution of 1-acetyl-4-piperidone (0.130 g, 0.920 mmol) and p-toluenesulfonic acid monohydrate (0.004 g, 0.02 mmol) in acetic acid (4 mL) was added 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol). The mixture was heated at 80° C. for 5 h. Then, the reaction was allowed to cool to room temperature and concentrated. The obtained residue was dissolved in methanol (25 mL) and the solution was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solution was filtered, and the filtrate was concentrated. The obtained residue was triturated with H2O. The obtained yellow solid was triturated with hot ethyl acetate to give the title compound (0.0407 g, 52%) as a yellow solid:
Reaction SMILES: C(O[C:6]([C:8]1[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[C:11]2[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=1>>[CH3:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:6]([C:8]2[CH:18]=[C:17]([O:19][CH:20]([CH3:21])[CH3:22])[C:11]3[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:25]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(CO)O2
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CO)O2

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (215a) and 3-amino-1-methyl-pyrazole. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1 H) 7.26-7.35 (m, 1 H) 6.95-7.05 (m, 1 H) 6.76-6.86 (m, 2 H) 4.93-5.08 (m, 1 H) 4.59-4.71 (m, 1 H) 3.84-3.91 (m, 1 H) 3.83 (s, 3 H) 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.89-3.02 (m, 1 H) 1.98 (t, J=6.44 Hz, 1 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C17H21N3O4 m/z 332.20 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[NH:13])[NH:11][OH:12])[CH:5]=1.C(N(C(C)C)CC)(C)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=O>C1COCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]1[O:12][N:11]=[C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:2])=[O:14])[N:13]=1
Reactant: COC(=O)c1cccc(C(=N)NO)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of 3-(N-Hydroxycarbamimidoyl)-benzoic acid methyl ester (60 g, 310 mmol) in anhydrous THF (200 mL) was added diisopropylethylamine (75 mL, 434 mmol) at 5° C., and then to the mixture was added 2-fluorobenzoyl chloride (48.1 mL, 403 mmol) over 20 min. The reaction mixture was stirred for 1 h at room temperature. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethylacetate (400 mL) and then washed with water (200 mL×2). The solvent was removed under reduced pressure and the desired product was crystallized in 60% ethylacetate in hexane to yield the desired product (81 g, 83% yield) as a white solid. 1H-NMR (CDCl3) δ 8.18 (1H), 8.03 (2H), 7.48 (2H), 7.18 (2H), 5.61 (2H), 3.82 (31-1).
Reaction SMILES: C(OC(N1CC(F)C[C@H]1C=C([C:16]1[CH2:22][C@H:21]2N([C:19](=O)[C@@H:20]2[C@H:23]([OH:25])C)[C:17]=1[C:27](OCC=C)=O)C)=O)C=C.N1CC[O:36]CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.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>[CH3:19][C:20]([C:23]([OH:36])=[O:25])=[CH:21][CH2:22][CH2:16][CH2:17][CH3:27]
Reactant: C1COCCN1
Reactant: C=CCOC(=O)C1=C(C(C)=C[C@@H]2CC(F)CN2C(=O)OCC=C)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCC=C(C)C(=O)O

Procedure:
To a solution of allyl (5R,6S)-3-[2-{(2S)-1-allyloxycarbonyl-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.7 g), morpholine (694 μl), and triphenylphosphine (199 mg) in tetrahydrofuran (30 ml) and ethanol (10 ml) was added tetrakis(triphenylphosphine)palladium(0) (263 mg) at room temperature. After stirring for an hour, the precipitate was filtered, washed in turn with dichloromethane (3 times) and acetone (twice), and dried under reduced pressure to give (5R,6S)-3-[2-{(2S)-4-fluoropyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1hydroxyethyl]-7-oxo-1-azabicyclo 3.2.0]hept-2-ene-2carboxylic acid (248 mg).