Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:28][CH2:27][C:26]4[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: COc1ccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1
Yield: 32 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-methoxyphenethyl bromide. Yield: 32%. 1H NMR (DMSO-d6, 400 MHz): δ2.11 (s, 3H), 2.38 (s, 3H), 2.78 (t, J=7.4 Hz, 2H), 3.50 (t, J=7.4 Hz, 2H), 3.69 (s, 3H), 4.02 (s, 2H), 5.16 (s, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 7.73 (s, 1H), 8.12 (s, 1H). MS M+H calculated 410.18. Found 410.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=2)[C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:29]=[CH:30][CH:31]=2)[C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:32])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)NCCO)c2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2cccc(C(=O)NCCO)c2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-hydroxyethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 8% of the corresponding Z isomer, MS (ESI+): m/z=472.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:32])([CH2:28][CH:29]1[CH2:31][CH2:30]1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[CH:29]1([CH2:28][C:20]([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:32])[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)C(C)(N)CC1CC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)(C)OC(=O)C(C)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and tert-butyl 2-amino-3-cyclopropyl-2-methyl-propanoate (example 186b) as starting materials and isolated (105 mg, 31%); MS (ESI, m/z): 443.6 (M+H+).
Reaction SMILES: ClC(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Br-:11].[Na+].CO.O.[CH3:16][N:17]([CH3:20])[CH:18]=[O:19]>>[Br-:11].[C:5]1([C:18]([N:17]([CH3:20])[CH3:16])=[O:19])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Phenyl N,N-dimethylformamide bromide was prepared by dropwise addition of phenyl chloroformate (6.5 ml; 50 mmol) to a stirred solution of sodium bromide (5.14 g; 50 mmol) in dimethylformamide at 0°-5° C. Sodium chloride precipitated, and the resulting suspension was stirred at 0°-5° C. for 4 hours and then at room temperature overnight. The mixture was cooled to 0° C. and 16-deacetoxy-16β-(acetylthio)fusidic acid acetoxymethyl ester (6.07 g; 10 mmol) was added with stirring. After stirring at 0°-5° C. for 4 hours, the mixture was left at room temperature for a further 4 days. On dilution of the stirred reaction mixture with methanol-water 1:1 (75 ml) an oily product precipitated, which was washed repeatedly by decantation with methanol-water 1:1 and finally taken up in ether, dried, and evaporated in vacuo. The amorphous residue thus obtained was purified by dry column chromatography on silica gel (petroleum ether-ethyl acetate 85:15) to give the desired compound as a colourless foam.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-])=O)[CH:27]=4)[CH:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[C].[Pd]>[NH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][NH:24][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=2)[N:19]=[CH:18][C:17]=1[CH2:20][C:21]([NH2:23])=[O:22]
Reactant: [H][H]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc(N)c1
Yield: 99.3 %

Procedure:
21 mg of 6-[(4-morpholinophenyl)amino]-4-[(3-nitrobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 102) was dissolved in 1 mL of acetic acid, to which 21 mg of 10% palladium carbon was added, and stirred in a hydrogen atmosphere at room temperature for 4 hours. The 10% palladium carbon was filtered off, and the solvent was evaporated to obtain 19.5 mg (100%) of the title compound as a light gray solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si]([O:36][CH2:37][CH:38]1[O:43][CH2:42][C:41]2=[N:44][CH:45]=[CH:46][N:40]2[CH2:39]1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>O1CCCC1>[N:44]1[CH:45]=[CH:46][N:40]2[CH2:39][CH:38]([CH2:37][OH:36])[O:43][CH2:42][C:41]=12
Reactant: CC(C)(C)[Si](OCC1Cn2ccnc2CO1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC1Cn2ccnc2CO1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Add tetra-N-butylammonium fluoride (1M in tetrahydrofuran; 13.98 mL; 3 equiv; 13.98 mmoles) to a solution of tert-butyl-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-ylmethoxy)-diphenyl-silane (6.96 g; 1.0 equiv; 17.73 mmoles) in tetrahydrofuran (100 mL) and stir for 1 hour. Load the solution directly onto an SCX ion-exchange column and elute with 15% methanol in dichloromethane followed by 20% ((2N ammonia in methanol) in dichloromethane) to afford (2 scx ion-exchange purifications were required) 6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-ylmethanol (2.59 g; 61%). MS (m/z): 155(M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:36][C:37]1[S:38][CH:39]=[N:40][N:41]=1)=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1nncs1
Yield: 84.6 %

Procedure:
Using the same procedure as in Example 1(i), 10 g of N-t-butoxycarbonyl-L-tryptophan, 3.3 g of triethylamine, 3.5 g of ethyl chlorocarbonate and 3.3 g of 2-amino-1,3,4-thiadiazole were reacted in 150 ml of chloroform to obtain 10.7 g (yield: 84%) of 2-(N-t-butoxycarbonyl-L-tryptophanylamino)-1,3,4-thiadiazole as light yellow powder of mp: 98°-101° C. (dec.) and [α]D20 : +41.0° (C=1.0, MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:41]=[CH:40][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:42])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:24]2[CH:25]=[C:20]([O:19][C:18]3[CH:40]=[CH:41][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:16][C:17]=3[F:42])[N:21]=[CH:22][N:23]=2)=[O:28])[CH2:30][CH2:31]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 2 h
Yield: 38 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.5 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyrimidine (150 mg) and (+)-10-camphorsulfonic acid (173 mg) in ethanol (3.5 ml) at room temperature, the mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the title compound (84.8 mg, 38%) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:11]([O:13]CC)=O)[CH:5]=[CH:4][N:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:11](=[O:13])[C:10]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=[CH:9][NH:8]2
Reactant: CCOC(=O)C(=CNc1ccnc(Cl)c1)c1ccc(Cl)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(Cl)c12

Procedure:
Solid ethyl α-[[(2-chloro-4-pyridinyl)amino]methylene]-(4-chlorophenyl)acetate (4.0 g) was added in portions to refluxing phenylether (50 mL). After 20 min at reflux, the reaction was allowed to cool and diluted with hexanes. The precipitate that formed was collected and washed with hexanes. Purification by preparative RPHPLC gave the title compound as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7](O)[C@H:5]([OH:6])[C@@H:3]1O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:16][CH:17]1[O:19][C@H:7]([CH2:5][O:6][C:11](=[O:12])[CH3:9])[C@@H:9]([O:10][C:2](=[O:1])[CH3:3])[C@H:11]([O:12][C:5](=[O:6])[CH3:7])[C@@H:18]1[O:10][C:2](=[O:1])[CH3:3])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 96.7 %

Procedure:
Analogously, as described in the literature [M. L. Wolfrom and A. Thompson in Methods in Carbohydrate Chemistry (R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Eds.), Academic Press, New York, Vol. II, 53, pp. 211-215, (1963)], the reaction of 150 g (832.5 mmol) of α,β-D-mannopyranose with a mixture that consists of 1500 ml of absolute pyridine and 1500 ml of acetic acid anhydride after working-up yields 315 g (96.7%) of the above-mentioned title compound as crude product in the form of a viscous and colorless oil. By 1H-NMR-spectroscopic study of the thus obtained title compound, it was possible to determine the α to β ratio of both anomers at 4:1. A separation of the α,β-anomers of the above-mentioned title compound can thus be eliminated in performing the subsequent reaction steps.
Reaction SMILES: [O:1]1[CH2:5][C:4](=O)[CH2:3][C:2]1=[O:7].[CH3:8][C:9]1([NH:14][C:15]([NH2:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:8][C:9]1([NH:14][C:15]([NH:17][C:4]2[CH2:5][O:1][C:2](=[O:7])[CH:3]=2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1COC(=O)C1
Reactant: CC1(NC(N)=O)CCCC1
Product: CC1(NC(=O)NC2=CC(=O)OC2)CCCC1
Yield: 47.6 %

Procedure:
Using the procedure described in Example 2 using 3 g of 2,4-furandione and 4 g of 1-methylcyclopentylurea there is obtained 3 g of 1-(1-methylcyclopentyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 170° C. (decomposition).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].O.[C:10]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[C:1]([O:8][CH3:10])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCC(=O)O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: O
Product: C=CCCCC(=O)OC
Yield: 84 %

Procedure:
5-Hexenoic acid (4.9 g, 42.9 mmol) was refluxed in 80 ml of methanol with catalytic p toluene sulfonic acid monohydrate for 40 hours. The solution was cooled and concentrated then poured into ether/water. The ether layer was dried over sodium sulfate and concentrated to give 4.6 g (35.9 mmol), 84% of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:15].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([NH:20][C:10](=[O:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[CH:5]=1)([CH3:14])[CH3:13])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CN
Reactant: COc1ccc(C(C)(C)C(=O)O)cc1C
Product: COc1ccc(C(C)(C)C(=O)NCC(C)C)cc1C
Yield: 64 %

Procedure:
Prepared in a similar manner to Example 35a starting from 2-(4-methoxy-3-methylphenyl)-2-methylpropanoic acid (example 50d) and isobutylamine. Yield: 64%. MS+H (264).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:8]([CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)([O:5]CC)=[O:4]>O.C(O)C>[F:27][C:23]1[CH:22]=[C:21]([CH:14]([CH2:8][C:3]([OH:5])=[O:4])[CH2:15][C:16]([OH:18])=[O:17])[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(c1cccc(F)c1)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(CC(=O)O)c1cccc(F)c1
Yield: 77.3 %

Procedure:
To a hot solution of sodium hydroxide (19.15 g, 0.479 mol) in water (50 mL) was added a solution of diethyl 2-carbethoxy-3-(3-fluorophenyl)glutarate (18.8 g, 0.0532 mol) in ethanol (36 ml). The resulting slurry was refluxed for 5 hrs. The mixture was poured into icewater and the ethanol was removed by spin evaporation in vacuo. The residual aqueous solution was acidified with concentrated hydrochloric acid (12 N) and the solution (200 mL) was extracted with ethyl acetate (3×300 ml). The ethyl acetate layers were combined, washed with water (50 ml) and the volatiles were removed by spin evaporation in vacuo to give a solid that was recrystallized from dichloromethane and hexanes to give 9.3 g (77%) of 3-(3-fluorophenyl)glutaric acid a white solid; m.p., 126-127.5° C.;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:13][C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=Cc1cnc2ccc(Br)cn12
Product: Cc1ccc(-c2ccc3ncc(C=O)n3c2)cn1
Yield: 40 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 6-methylpyridin-3-ylboronic acid. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): δ 10.0 (s, 1H), 9.74 (s, 1H), 8.79 (d, 1H, J=1.8 Hz), 8.38 (s, 1H), 7.93-7.78 (m, 4H), 7.33 (d, 1H, J=8.1 Hz), 2.66 (s, 3H); MS: m/z 238(M+1)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:7])=[CH2:6])=[O:3].[NH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH:25]=3)[C:15]([CH3:19])=[N:16]2)=[CH:11][N:10]=1>N1C=CC=CC=1>[CH2:6]=[C:5]([O:4][C:2](=[O:3])[NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:20]3[CH:21]=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][CH2:30][CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])[CH:25]=3)[C:15]([CH3:19])=[N:16]2)=[CH:11][N:10]=1)[CH3:7]
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1nc2cc(N)ncc2cc1-c1ccc(F)c(NC(=O)NCCC(C)(C)C)c1
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc2nc(C)c(-c3ccc(F)c(NC(=O)NCCC(C)(C)C)c3)cc2cn1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
Add isopropenyl chloroformate (0.193 mL, 1.769 mmol) to a 0° C. solution of 1-(5-(7-amino-2-methyl-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,3-dimethylbutyl)urea (0.636 g, 1.608 mmol) in pyridine (10 mL) and stir the mixture for 1 h as it warms to RT. Add water, extract with DCM (3×), dry the combined organics over MgSO4 and concentrate to dryness to afford the title compound (585 mg, 76%). MS(ESI) m/z: 480.2 (M+H+).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=O)[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].P(Cl)(Cl)[Cl:21]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:21][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: ClP(Cl)Cl
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Reaction time: 5 h

Procedure:
Benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (26 mg, 0.1 mmol) in anhydrous DMF (0.5 ml) containing PCl3 (27 mg, 0.2 mmol) is kept at 25° C. for 5 hrs. The mixture is diluted with toluene (5 ml), washed with H2O (5×1 ml) 5% HCl (2 ml), 5% NaHCO3 (2 ml) and brine, dried with MgSO4, and filtered. Evaporation of the solvent in vacuo provides crude benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCN3CCOCC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23, (586 mg; 1.41 mmol; 1 eq) is dissolved in anhydrous DCM (15 ml). The reaction is put under nitrogen. Then triethylamine (1.96 ml; 14.1 mmol; 10 eq) and 2-morpholin-4-yl-ethylamine (367 mg; 2.82 mmol; 2 eq) are added successively and the reaction mixture is stirred at room temperature for 30 minutes. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording the title compound (100 mg; 14%).
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[CH3:22][C:23]1[N:27]=[C:26]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[O:25][N:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:26]2[O:25][N:24]=[C:23]([CH3:22])[N:27]=2)[CH:29]=1)([O-:21])=[O:20]
Reactant: Cc1noc(-c2cccc(N)c2)n1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: Cc1noc(-c2cccc(Nc3ccc4ccccc4c3[N+](=O)[O-])c2)n1

Procedure:
1-Nitronaphthalen-2-yl triflate and 3-(3-methyl-[1,2,4]oxadiazol-5-yl)aniline were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO.[H][H]>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2)CC1
Yield: 93.1 %

Procedure:
1-Methyl-4-(4-nitro-benzyl)-piperazine (3.70 g, 15.7 mmol) was dissolved in Methanol (40.0 mL, 987 mmol) and was carefully added to a Parr vessel containing 10% Palladium on Carbon (1.00 g, 74.9 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 3.00 g of 4-(4-Methyl-piperazin-1-ylmethyl)-phenylamine without further purification. (M+H)=205.96.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:15]=2[N:16]=[C:17]([C:19]2[O:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[O:23]1[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:15]=3[N:16]=2)=[CH:20][CH:21]=[N:22]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc(Cl)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 37 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-chlorobenzenesulfonyl chloride under the conditions used in example 2 giving 37% of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:18][C@@H:19]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:18][C@H:19]2[NH:20][C:21](=[O:24])[CH2:22][CH2:23]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC[C@@H](CN2CCCCC2)N1
Yield: 100 %

Procedure:
Piperidine a14 (0.7 g, 8.3 mmol, 1.5 eq) is added to a suspension of [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonate a13 (1.5 g, 5.56 mmol, 1 eq) and potassium carbonate (1.5 g, 11.1 mmol, 2 eq) in acetonitrile (50 ml), and the mixture is stirred at reflux overnight. Potassium carbonate is filtered and the solvent is removed in vacuo. The residue is dissolved in a minimum of dichloromethane, then the organic layer is sonicated and heated to precipitate a white solid which is filtered. The liquid phase is concentrated in vacuo to give 1 g of (5S)-5-(piperidin-1-ylmethyl)pyrrolidin-2-one a15 as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>CN(C)C=O.C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([Cl:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)s1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(Br)s1
Yield: 99.1 %

Procedure:
A mixture of 5-bromothiophene-2-carboxylic acid (300 mg 1.45 mmol), thionyl chloride (423 μL, 5.80 mmol), and N,N-dimethylformamide (1 drop) was dissolved in chloroform (3 mL), and refluxed for 1 hour. After cooling down, the reaction mixture was concentrated under reduced pressure to give the titled reference compound (324 mg) as a pale yellow solid. (Yield 99%)