Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[OH:43])[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][CH:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[OH:43])[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:19]1)=[O:17]
Reactant: CCCCOC1(c2ccccc2C)CN(C(=O)C(Cc2ccc(OC)cc2O)NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2C)CN(C(=O)C(N)Cc2ccc(OC)cc2O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid is added to 220 mg (0.4 mmol) of tert-butyl[2-(3-butoxy-3-o-tolyl-azetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxo-ethyl]carbamate in 2 ml of dichloromethane. After stirring for 1 hour at ambient temperature, the reaction medium is concentrated under vacuum. 250 mg of 2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-one trifluoroacetate are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]CC)=O)[C:5]([N+:13]([O-])=O)=[C:4]([N:16]([CH2:23][C:24]([O:26]CC)=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.Cl[C:30]1N=[C:34]([C:36](OCC)=O)[C:33]([N+]([O-])=O)=[C:32](Cl)[N:31]=1.C1([NH:51]CC(OCC)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[O:26]=[C:24]1[CH2:23][N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]2[N:3]=[C:2]([C:34]3[CH:36]=[CH:30][N:31]=[CH:32][CH:33]=3)[N:7]=[C:6]([C:8]([NH2:51])=[O:10])[C:5]=2[NH:13]1
Reactant: CCOC(=O)CN(c1ccccc1)c1nc(Cl)nc(C(=O)OCC)c1[N+](=O)[O-]
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1nc(-c2ccncc2)nc2c1NC(=O)CN2c1ccccc1
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Ethyl 2-chloro-6-((2-ethoxy-2-oxoethyl)(phenyl)amino)-5-nitropyrimidine-4-carboxylate. A solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.5 g, 5.67 mmol) in anhydrous tetrahydrofuran (20 mL) was chilled to −78° C. under nitrogen. A solution of ethyl 2-(phenylamino)acetate (1.1 g, 6.22 mmol) and diisopropylethylamine (3.0 mL, 17.01 mmol) in anhydrous tetrahydrofuran (10 mL) was then added dropwise, with stirring, over 10 min. The reaction was stirred at −78° C. for 6 h, followed by addition of aqueous sodium bicarbonate solution (saturated, 10 mL). The mixture was extracted with ethyl acetate (3×10 mL). The organic phase was dried over sodium sulfate and concentrated to a residue which was purified by chromatography on a normal phase silica gel column (0-10% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (1.1 g, 2.89 mmol, 41% yield). MS (ESI) m/z 409.5 [M+1]+.
Reaction SMILES: CC(C)([O-])C.[Na+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[Br:13][CH:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: CCCCCC(Br)Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCCCN1CCOCC1
Temperature: 50 °C

Procedure:
Under nitrogen 250 ml anhydrous THF were added to 37 g (1.1 eq, 385 mmol) sodium tert-butoxide. Then 30.45 g (1 eq, 350 mmol) morpholine were added neat. The suspension was heated to 50° C. for 1 h. After cooling to RT, 1.21 anhydrous THF and 85.29 g (1 eq, 350 mmol) dibromohexane in ˜150 ml anhydrous THF were added. After 1 h at RT the mixture was heated to 85° C. over night. The overstanding solution was decanted and all volatiles removed in vacuo. The residue was dissolved in ether and water and the organic layer extracted with 2M hydrochloric acid. After dilution with water and ether, KOH flakes were added under vigorous stirring and cooling until pH=10. After phase separation, the aqueous layer was extracted with ether. The combined organic layers were dried over brine and MgSO4 and all volatiles removed to yield 40 g. Further purification by column chromatography (70% hexane, 30% ethyl acetate, 5% triethylamine) yielded 14.56 g, 99% by GCMS. 1H-NMR (400 MHz, CDCl3): [ppm]=3.71 (t, J=4 Hz, 4H), 3.41 (t, J=6.8 Hz, 2H), 2.42 (t, J=4 Hz, 4H), 2.32 (t, J=7.6 Hz, 2H), 1.48 (m, 4H), 1.34 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH:21][NH2:22]>C(O)CCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[C:12](=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:21]([CH3:20])[N:22]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNN
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Solvent: CCCCO
Product: CC(=O)N1CCC(c2nn(C)c3cc(F)ccc23)CC1
Yield: 108.7 %

Procedure:
A solution of 5.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine, 1.2 g of methylhydrazine and 50 ml of n-butanol was heated under reflux for 16 hrs. After cooling, the solvent was removed in vacuo and the residue was diluted with water. The aqueous mixture was made basic with ammonium hydroxide and extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to yield 5.6 g of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1-methyl-1H-indazole as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:23][C:24](=[O:28])[CH:25](Br)[CH3:26])[CH3:22].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a suspension of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added 2-bromo-propionic acid ethyl ester (13 ml) and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled to 0° C., and toluene (100 ml) and water (150 ml) were successively added dropwise. The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml). The combined organic layer was successively washed once with 10% aqueous potassium carbonate (50 ml), twice with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21.6 g).
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[S:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1.C(#N)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(OCC)C>[CH3:21][O:20][C:18]1[N:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([NH:13][C:11](=[S:12])[NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[N:19]=1
Reactant: COc1nc(N)nc(OC)n1
Reactant: O=S(=O)(N=C=S)c1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CC#N
Solvent: CCOCC
Product: COc1nc(NC(=S)NS(=O)(=O)c2ccccc2)nc(OC)n1

Procedure:
A mixture containing 20 g of benzenesulfonyl isothiocyanate, 15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine, 250 ml of acetonitrile and a catalytic amount of dibutyltin dilaurate was stirred for 24 hours. After filtration to remove unreacted triazine, the evaporation of the acetonitrile yielded a gummy residue. Trituration of this material with ethyl ether resulted in the precipitation of the desired compound, which was isolated by filtration and melted at 148°-150° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:8][C:9]([F:28])([F:27])[C:10]1[C:25]([Cl:26])=[CH:24][C:13]2[C:14](=O)[CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[S:18][C:12]=2[CH:11]=1.O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:8][C:9]([F:28])([F:27])[C:10]1[C:25]([Cl:26])=[CH:24][C:13]2[C:14]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[S:18][C:12]=2[CH:11]=1
Reactant: CN1CCNCC1
Reactant: O=C1Cc2ccccc2Sc2cc(C(F)(F)F)c(Cl)cc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(C(F)(F)F)c(Cl)cc32)CC1
Yield: 88 %

Procedure:
1-Methylpiperazine (8.0 g) was added to a solution of 7-trifluoromethyl-8-chlorodibenzo(b,f)thiepine-10(11H)-one (the preparation of which is described in the preceding Example) (5.17 g) in benzene (40 ml). Then, titanium tetrachloride (1.63 g) in benzene (10 ml) was added dropwise, the mixture refluxed for 24 hours while stirring, cooled and decomposed with water (60 ml). The separated solid was filtered and washed with benzene and water. The benzene layer of the filtrate was separated, washed with water, filtered with charcoal and dried over magnesium sulfate. Evaporation of the benzene yielded 5.68 g (88%) of the crude enamine base, named in the heading of this Example. Neutralization of this base with methanesulfonic acid in ethanol, followed by addition of ether, yielded the crystalline methanesulfonate which crystallized from acetone as a monohydrate; m.p. 267°-270° C.
Reaction SMILES: N1N=C(C2C=CC=CC=2C([N:14]2[CH2:18][CH:17]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]3[CH2:15]2)=O)NC=1.[N:29]1[N:30]([C:34]2[C:35]([C:40]([OH:42])=O)=[N:36][CH:37]=[CH:38][CH:39]=2)[N:31]=[CH:32][CH:33]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[N:31]1[N:30]([C:34]2[C:35]([C:40]([N:14]3[CH2:18][CH:17]4[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH:16]4[CH2:15]3)=[O:42])=[N:36][CH:37]=[CH:38][CH:39]=2)[N:29]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ncccc3-n3nccn3)CC2C1

Procedure:
tert-Butyl 5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate was prepared in a manner analogous to Intermediate 59 substituting 3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid (Intermediate 72) for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for C19H24N6O3, 384.19; m/z found, 385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Br[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH:30](O)([CH3:32])[CH3:31]>O>[CH3:31][CH:30]([O:21][C:19]([C:18]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])=[CH:15][CH:14]=1)([CH3:23])[CH3:22])=[O:20])[CH3:32]
Reactant: CC(C)(Br)C(=O)O
Reactant: CC(C)O
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 110 °C
Yield: 77 %

Procedure:
100 g (0.43 mol) of (4-chlorophenyl)(4-hydroxyphenyl)methanone and 165 g (0.79 mol) of the 1-methylethyl ester of 2-bromo-2-methylpropanoic acid are introduced, under a nitrogen atmosphere, into a 3-necked round-bottomed flask equipped with a stirrer and a condenser. The reaction medium is heated to 110° C. and a solution of 50 g (0.36 mol) of potassium carbonate in 50 ml of demineralized water is then added slowly over a period of 20 minutes, with distillation taking place at 100° C. The distillate separates out into 2 phases. The lower phase is recycled into the reaction medium. After heating at 110°-112° C. for 1.5 h, the reaction medium is brought to 140° C. and a temperature of 140°-145° C. is maintained for 4 hours. The reaction medium is then cooled to about 90° C. and 210 ml of 80% isopropyl alcohol are added. The mixture is then left to cool for 12 h, with stirring, after which the suspension obtained is filtered at 0° C. The precipitate is washed with 4 times 200 ml of demineralized water and then recrystallized from propan-2-ol to give 119.5 g (yield=77%) of fenofibrate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:22])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)C=Cc2cccc(O)c2)cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Product: COC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Reaction time: 1.5 h
Yield: 26 %
Yield: 64 %

Procedure:
A mixture of 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)-2-propenyl]benzoic acid, methyl ester (250 mg, 0.8 mmol) and 10% palladium-on-charcoal (25 mg) in ethyl acetate (5 mL) was hydrogenated at atmospheric pressure for 90 min. The reaction mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The solvent was evaporated and the residue chromatographed (20-50% ethyl acetate/hexanes) to give 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid, methyl ester (160 mg, 64%) and 2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propyl]benzoic acid, methyl ester (65 mg, 26%). The alcohol was obtained as a racemic mixture and was not resolved.
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H:4]([O:20][C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]3N)[C@H]2O)[C@@H:3]([OH:41])[C@@H:2]1[NH2:42].OS(O)(=O)=O.[BrH:48]>>[CH2:1]1[C@H:2]([NH2:42])[C@@H:3]([OH:41])[C@H:4]([OH:20])[C@@H:5]([OH:8])[C@@H:6]1[NH2:7].[BrH:48]
Reactant: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Agent: Br
Agent: O=S(=O)(O)O
Product: N[C@@H]1C[C@H](N)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 100 °C
Reaction time: 10 h
Yield: 61 %

Procedure:
A solution of neomycin sulfate (20 g, 20.8 mmol) in HBr (150 mL, 48%) is stirred under reflux at 100° C. for 40 hours. The solution is concentrated to dryness at 60° C. under reduced pressure. The residue is dissolved into water (H2O) (100 mL), and activated charcoal (10 g) is added. After stirring at room temperature for 10 hours, the charcoal is removed by filtration through Celite, and the solution is concentrated to a syrup. Methanol (100 mL) is added and the mixture is stirred for 2 hours t room temperature. The solid product is filtered to give 2-deoxystreptamine hydrobromide 3 (4.1 g, 61%). Rf: 0.2 (CH3OH/NH4OH=4:1); 1H-NMR (D2O, 200 MHZ): d 1.95 (1H, ddd), 2.5 (1H, m), 3.2-3.6 (9H, m); 13C-NMR (D2O, 200 MHZ): d 40.0, 65.0, 87.2, 89.5. Ref. Georgiadas, M. P.; Constantinou-Kokotou, V. J. Carbohydr. Chem. 1991, 10, 739-746.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH:3]([C:9]([C:11]1[CH:25]=[CH:24][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:13]=2[CH:12]=1)=[O:10])[CH2:4][C:5]([O:7]C)=[O:6].[OH-].[Li+].O.Cl>O1CCOCC1>[CH3:1][CH:2]([CH3:26])[CH:3]([C:9]([C:11]1[CH:25]=[CH:24][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:13]=2[CH:12]=1)=[O:10])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CC(C(=O)c1ccc2nc(-c3ccccc3)oc2c1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(CC(=O)O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
100 mg (285 μmol) methyl 4-methyl-3-(2-phenyl-benzoxazole-6-carbonyl)-pentanoate, 10 mg (418 μmol) lithium hydroxide, 1 ml of water and 1 ml dioxane are stirred for 24 h at RT. The reaction mixture is acidified with conc. hydrochloric acid and extracted with diethyl ether, the org. phase is dried on magnesium sulphate and the solv. is eliminated by rotary evaporation i.V.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[CH3:21][N:22]=[C:23]=[O:24].[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29](C(O)=O)=[C:28]([O:36][CH3:37])[CH:27]=1>>[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:23]([NH:22][CH3:21])=[O:24])[CH2:11]2)=[O:7])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CNC(=O)NCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
5-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (0.84 g) as starting compound was reacted and treated in the same manner as in Example 34 using methyl isocyanate (0.26 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.58 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(5-(3-methylureido)pentyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([Cl:12])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:19]1[CH:23]=[CH:22][CH:21]=[N:20]1>CN(C=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=1
Reactant: Nc1nc2cc(Cl)cc(Cl)n2n1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc2cc(Cl)cc(-n3cccn3)n2n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
5,7-Dichloro[1,2,4]triazolo[1,5-a]pyridin-2-amine (Intermediate 15) (0.5 g, 2.46 mmol), cesium carbonate (1.6 g, 4.93 mmol) and pyrazole (0.5 g, 7.39 mmol) was suspended in DMF (10 mL) and stirred at 70° C. for 2 h after which time LCMS showed desired product formation. The reaction mixture was filtered through celite, which was washed with further DMF and the resultant green/brown solution was concentrated in vacuo to give a brown residue, which was partitioned between 10% IPA/DCM (20 mL) and water (10 mL), the organic layer was separated and the aqueous extracted with further 10% IPA/DCM (2×10 mL). The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo to give the desired product as a brown solid (0.4 g, 69%). 1H NMR (DMSO) δ 9.16 (d, J=2.6 Hz, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 6.72 (dd, J=2.4, 1.9 Hz, 1H), 6.46 (s, 2H). MS: 235.12 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:29]([O:48][NH2:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C=O)C>[CH3:17][O:16][C:14](=[O:15])[CH:8]([CH2:9][CH2:10][C:11](=[O:13])[NH:49][O:48][C:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:18]
Reactant: NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(CCC(=O)O)CC(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)C(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 64 (1.10 g, 4.19 mmol) and HOBt (0.70 g, 5.03 mmol) in DMF (5 mL) were added O-trityl hydroxylamine (1.82 g, 6.28 mmol) and DIC (800 μL), respectively. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was partitioned between HCl (1N, excess) and ethyl acetate. The aqueous phase was extracted several times with ethyl acetate. The recombined organic layer was washed with brine, saturated sodium bicarbonate, and brine. The solvent was evaporated following drying over sodium sulfate, and the crude was flashed with 20–30% ethyl acetate in hexanes. 1H-NMR(CDCl3, 400 MH: 1.42(s, 9H); 1.58, 2.14, 2.47(3 m, 7H); 3.69(s, 3H); 7.34(m, 15H); 7.88(d, broad, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O:27][C:28]([C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[S:35]([C:38]1[N:42]2[C@:43]([CH3:68])([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:58][CH:57]=3)[C:44](=[O:54])[N:45]([C:46]3[CH:51]=[C:50]([Cl:52])[CH:49]=[C:48]([Cl:53])[CH:47]=3)[C:41]2=[N:40][CH:39]=1)(=[O:37])=[O:36])=O)(C)(C)C.[NH:69]1[CH2:78][CH2:77][CH:72]([C:73]([O:75]C)=[O:74])[CH2:71][CH2:70]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[Cl:53][C:48]1[CH:47]=[C:46]([N:45]2[C:41]3=[N:40][CH:39]=[C:38]([S:35]([N:31]4[CH2:32][CH2:33][CH2:34][C@H:30]4[C:28]([N:69]4[CH2:78][CH2:77][CH:72]([C:73]([OH:75])=[O:74])[CH2:71][CH2:70]4)=[O:27])(=[O:36])=[O:37])[N:42]3[C@:43]([CH3:68])([CH2:55][C:56]3[CH:61]=[CH:60][C:59]([C:62]4[CH:63]=[N:64][CH:65]=[N:66][CH:67]=4)=[CH:58][CH:57]=3)[C:44]2=[O:54])[CH:51]=[C:50]([Cl:52])[CH:49]=1
Reactant: COC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3cncnc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(-c3cncnc3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(=O)N3CCC(C(=O)O)CC3)n21
Temperature: 95 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
TBTU (0.12 g), (S)-1-[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (Example 14) (0.15 g) and methyl isonipecotate (0.041 g), followed by DIPEA (0.10 mL), were combined in 1% DMF-CH2Cl2 (10.1 mL) at room temperature and the solution was stirred for 1 h. The reaction was diluted with CH2Cl2, poured into 1N HCl, and extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3 followed by H2O. The organic phase was dried (Na2SO4), filtered and concentrated. The resultant residue was re-dissolved in 30% HBr—AcOH and heated to 95° C. for 3 h. Following aqueous workup, the organic layer was dried (Na2SO4), filtered, concentrated, and the residue was purified by silica gel chromatography to afford the title compound (0.099 g) (738.2, M+1).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.O[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([S:4][C:5]2[CH:6]=[CH:7][C:8](/[C:11](/[C:15]3[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)=[CH:12]/[CH2:13][O:14][C:23]3[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=3)=[CH:9][CH:10]=2)[CH2:2][CH2:3]1
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(SC2CC2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The above allyl alcohol (3.40 g, 8.30 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (1.79 g, 9.13 mmol; compound VÚFB-21004) and triphenylphosphine (2.5 g, 9.55 mmol) were dissolved in a mixture of anhydrous toluene (38 mL) and tetrahydrofuran (13 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (1.88 mL, 9.55 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and then was stirred overnight. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1) affording methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate as yellowish oil.