Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([O:23][CH2:24][C:25]#[N:26])[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].[OH-].[Na+].Cl>CN(C=O)C.O>[CH2:1]([C:8]1[O:9][C:10]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([O:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)[CH:17]=[CH:16]3)=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc2cc(-c3cnc(Cc4ccccc4)o3)ccc2c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cc2ncc(-c3ccc4cc(OCc5nnn[nH]5)ccc4c3)o2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
A mixture of [6-(2-benzyl-oxazol-5-yl)-naphthalen-2-yloxy]-acetonitrile (618 mg, 1.82 mmol), prepared in the previous step, sodium azide (355 mg, 5.46 mmol) and ammonium chloride (312 mg, 5.83 mmol) in 50 mL of DMF was stirred under nitrogen at 100° C. for 5 h. Following the reaction by MS, starting material remained. Additional sodium azide (351 mg, 5.44 mmol) and ammonium chloride (316 mg, 5.85 mmol) were added and the reaction stirred at 100° C. for two more hours. The reaction was at first diluted with 10 ml of H2O, then was made basic with 1N NaOH and finally acidified with 1N HCl. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (568 mg, 82%) as a white solid, mp 227-228° C. Elemental Analysis for C22H17N5O2+0.37 H2O Calc'd: C, 67.74; H, 4.58; N, 17.95. Found: C, 67.84; H, 4.33; N, 18.09
Reaction SMILES: C([C:9]1([I:20])[C:17]([I:18])=[CH:16][C:15]([I:19])=[CH:14][CH:10]1[C:11]([O-:13])=[O:12])CCCCCCC.IC1C(I)=CC(I)=CC=1C(Cl)=O.IC1C(I)=CC(I)=CC=1C(O)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:58][C:59]([F:78])([C:63]([F:77])([F:76])[C:64]([F:75])([F:74])[C:65]([F:73])([F:72])[C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:60](O)[CH3:61].CN(C1C=CC=CN=1)C>ClCCl>[I:20][C:9]1[C:17]([I:18])=[CH:16][C:15]([I:19])=[CH:14][C:10]=1[C:11]([O:13][CH:60]([C:59]([F:58])([F:78])[C:63]([F:76])([F:77])[C:64]([F:74])([F:75])[C:65]([F:72])([F:73])[C:66]([F:70])([F:71])[CH:67]([F:68])[F:69])[CH3:61])=[O:12]
Reactant: CCCCCCCCC1(I)C(I)=CC(I)=CC1C(=O)[O-]
Reactant: CC(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1cc(I)cc(I)c1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OC(=O)c1cc(I)cc(I)c1I)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Using the same procedure as for 2-octyl-2,3,5-triiodobenzoate, 2,3,5-triiodobenzoyl chloride was prepared from 2.00 g of 2,3,5-triiodobenzoic acid and 2.54 g of oxalyl chloride in dry dichloromethane. The 2,3,5-triiodobenzoyl chloride was dissolved in 8 ml of dry dichloromethane. The solution was cooled to 0° C. and 0.810 g (8.00 mmol) of triethylamine was added. The brown solution was placed under nitrogen before 1.52 g (4.40 mmol) of 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluoro-2-octanol was added dropwise. Dimethylaminopyridine (0.049 g, 0.400 mmol) was added and the resulting solution was stirred at room temperature for 18 hrs. The brown solution was then partitioned between 100 ml of dichloromethane and 50 ml of 1M HCl. The dichloromethane layer was washed with saturated NaHCO3 solution (50 ml) and brine (25 ml). The solution was dried over Na2SO4 and concentrated in vacuo to yield 3.11 g of a brown oil. The oil was purified by flash chromatography using 125 g of silica gel and 4% ethyl acetate/hexane as the eluent. The first 475 ml to elute contained nothing, while the pure product eluted with the next 200 ml. Concentration in vacuo afforded 2.36 g (71%) of the product as a colorless oil which slowly solidified to a white, waxy solid. Mp. 32°-35° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7]>>[OH:5][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[CH2:9][CH2:8][C:6]2=[O:7]
Reactant: O=C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2c(O)cccc21

Procedure:
4-Hydroxy-1-indanone (76) was synthesized by aluminum chloride induced re-cyclization of dihydrocumarin (75), according to Org. Lett., 2007, 9(15), p. 2915-2918. The reaction was performed on 100 g of (75) to furnish (76) with 85% yield.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:2].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(OCC)(=O)C>[CH2:1]([C:3]1([C:13]2[N:14]=[CH:15][N:16]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=3)[CH:17]=2)[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:2]
Reactant: CCC1(c2c[nH]cn2)Cc2ccccc2C1=O
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCC1(c2cn(Cc3ccc(Cl)cc3)cn2)Cc2ccccc2C1=O
Yield: 74 %

Procedure:
2-ethyl-2-(1H-imidazol-4-yl)-1-indanone and 4-chlorobenzyl chloride were reacted at 60° C. as described in example 5. The yield was 74%. The hydrochloride was prepared in ethyl acetate, m.p. 150°-154° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[C:18]([C:19]3[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1.[BH4-].[Na+]>O1CCCC1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:18]([C:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:25][CH:26]=1
Reactant: O=C1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A suspension of 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enone (791 mg, 2.304 mmol, Example 1) in Tetrahydrofuran (150 mL) and Methanol (15.00 mL) was cooled to 0° C. under nitrogen, and was treated with sodium borohydride (349 mg, 9.21 mmol, 4.0 equiv) in 4 lots over 15 min. The reaction was warmed to 23° C. and was stirred under nitrogen. After 24 h, the reaction was quenched with saturated ammonium chloride solution (15 mL). The suspension was diluted with EtOAc (250 mL) and washed with saturated ammonium chloride solution (100 mL) and brine (100 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 1-4% methanol/dichloromethane), affording 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:22])[C:16]=3[C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:43])C(=O)C1>C(Cl)Cl>[NH2:22][C:21]1[C:16]2[C:15]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:27][CH:28]=3)=[C:14]([Cl:43])[N:13]([C@@H:10]3[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2c(Cl)c(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.1 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (2) (350 mg, 0.74 mmol) in DCM (10.0 mL) was added NCS (198 mg, 1.48 mmol). After the mixture was stirred at r.t. for 6 hr the reaction solution was partitioned between DCM (20.0 mL) and water (20.0 mL). The layers were separated and the organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatographic (silica gel, 0-50% ethyl acetate in a mixture of petroleum ether and DCM (1:1)) to afford (R)-tert-butyl 3-(4-amino-6-chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (6) (150 mg, 40% yield) as a yellow oil. LC-MS (ESI): m/z (M/M+2) 506.1/508.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[N:8][N:9]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOC1
Yield: 76.7 %

Procedure:
A solution of 4-methoxy-1-(tetrahydrofuran-3-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (225 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (260 mg), tetrakis(triphenylphosphine)palladium(0) (70.8 mg) and 2M aqueous sodium carbonate solution (1.53 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (176 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.Cl[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>CN(C)C=O>[NH:32]([C:30]([CH2:29][NH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:6][CH2:5]1)=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=C(CCl)Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CNC1CCN(CCCC(=O)c2ccccc2)CC1)Nc1ccccc1
Reaction time: 48 h

Procedure:
4-Amino -1-(4-phenyl-4-oxobutyl) piperidine dihydrochloride (1.75g) was suspended in dimethylformamide (15 ml) containing triethylamine (3 ml) and chloroacetanilide (0.85G) added. The mixture was stirred for 48 hours and the precipitate of Et3N.HC1 filtered off. The filtrate was poured into water and the solid product filtered off and recrystallised from EtOH/H2O to give the title compound (1.35g). This was converted to the hydrochloride (1.35g) by treatment with EtOH-HC1 and Et2O, m.p. 255.1°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCc1nc2ccc(Cl)cc2n1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCn2c(CCNC(=O)OC(C)(C)C)nc3ccc(Cl)cc32)cc1

Procedure:
A solution of 1.5 g. (4.6 mmole) of 1-(2-hydroxy ethyl)-2-(2-t-butoxycarbonylaminoethyl)-6-chlorobenzimidazole prepared in Step B. above and 1.0 g. (5.5 mmole) p-toluenesulfonyl chloride in 7.5 ml. of dry pyridine is heated at 50° C. for 2 hours. After cooling the reaction mixture is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic extracts are dried with calcium sulfate and concentrated to remove solvent. The remaining pyridine is removed by azeotroping with toluene. The desired product, 1.6 g. (70%), is obtained as a crystalline solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-:20])=[O:19])=[C:10]([CH:17]=1)[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([N+:18]([O-:20])=[O:19])=[C:10]([CH:17]=1)[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C=CCOC(=O)c1cc(N)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(NC(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of acetyl chloride (3.18 g, 40.5 mM) in dichloromethane (10 ml) under an argon atmosphere was added at 0° to a solution of allyl 5-amino-2-nitrobenzoate (3.0 g, 13.5 mM) in dichloromethane (30 ml). After addition of a solution of triethylamine (1.88 ml, 13.5 mM) in dichloromethane (10 ml) the mixture was stirred at ambient temperature overnight. The solvent was evaporated and the residue purified by chromatography on silica. Elution with ethyl acetate/petroleum ether (50/50) gave allyl 5-acetamido-2-nitrobenzoate (3.36 g, 94%).
Reaction SMILES: Br[C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CN(C)CCN(C)C>C1(C)C=CC=CC=1>[C:3]([OH:5])(=[O:4])[CH:2]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Agent: CN(C)CCN(C)C
Solvent: Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1

Procedure:
5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of toluene and treated at room temperature with 1.39 g of tetramethylethylene-diamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-bromo-3-phenylpropionic acid had reacted completely to give cinnamic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(C(=O)O)CC2)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCC(C(=O)N3CCOCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
To a solution of 1-(3-methoxy-4-nitrophenyl)piperidine-4-carboxylic acid (Preparation 205, 150 mg, 0.535 mmol) in DMF (5 mL) was added morpholine (0.07 mL, 0.803 mmol), DIPEA (0.19 mL, 1.070 mmol) and HATU (244 mg, 0.642 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (30 mL) and EtOAc (30 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in EtOAc to afford the title compound (166 mg, 89%).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:43])[C:31](OC3C=CC([N+]([O-])=O)=CC=3)=[O:32])[CH:25]=2)=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10].O>CN(C)C=O>[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[N:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:43])[C:31]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:32])[CH:25]=2)=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10]
Reactant: CCCCCCCN
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)C(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cn2)c1
Temperature: 80 °C
Yield: 43.9 %

Procedure:
70 μl (0.45 mmol) of heptylamine are added to a solution of 110 mg (0.25 mmol) of methyl 2(S)-ethoxy-3-(6-{3-[methyl(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)propanoate in 3 ml of dimethylformamide. The reaction medium is heated at 80° C. for 3 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 6/4 and then 5/5 heptane/ethyl acetate mixture. 50 mg (50%) of methyl 2(S)-ethoxy-3-{6-[3-(3-heptyl-1-methylureido)phenyl]pyrid-3-yl}propanoate are obtained.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:5]=1[CH2:6][NH:7][N:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]CC)=[O:18])[CH:15]=[CH:16][C:11]=2[N:10]([CH3:22])[C:9]1=[O:23].C(O)C.O1CCCC1>O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:10]([CH3:22])[C:9](=[O:23])[N:8]([NH:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:4]=3[Cl:3])[C:12]=2[CH:13]=1)([OH:19])=[O:18]
Reactant: CCOC(=O)c1ccc2c(c1)n(NCc1ccc(Cl)cc1Cl)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(=O)n(NCc2ccc(Cl)cc2Cl)c2cc(C(=O)O)ccc21
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
Ten percent sodium hydroxide (0.650 g) was added to a mixture of 1-(2,4-dichlorobenzylamino)-6-(ethoxycarbonyl)-3-methyl-2-benzimidazolone (0.308 g), ethanol (4 ml), tetrahydrofuran (8 ml) and water (4 ml), and the mixture was stirred at 60° C. for 2.5 hr. A part of the reaction mixture was concentrated, and neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The crystals precipitated were filtered and dried to give the objective compound (0.276 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)=[C:4]([CH:3]=1)[CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCOC(=O)Cl
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Solvent: C1CCOC1
Product: CCCOC(=O)NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (500 mg, 0.89 mmol) and TEA (360 mg, 3.6 mmol) in THF (200 mL) at −20° C. was slowly added propyl chloroformate (108 mg, 0.89 mmol) in THF (10 mL). Then the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 u; liquid phase: [A-H2O+0.025% TFA; B-MeCN] B %: 15%-40%, 25 min) to give the title compound (246 mg, 46%) as TFA salt. 1H NMR DMSO 400 MHz δ 9.99 (s, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.42 (s, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 6.48 (s, 1H), 6.35 (q, 1H), 4.84 (s, 2H), 4.50 (s, 2H), 3.93 (q, 2H), 1.57 (q, 2H), 0.63 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](#[N:20])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C:18]#[N:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: N#C[C@H]1CCN(Cc2ccccc2)C1
Temperature: 65 °C
Yield: 85 %

Procedure:
(R)-1-Benzyl-3-mesyloxypyrrolidine (5.0 g, 20 mmol) was dissolved in acetonitrile (6 mL) and tetrabutylammonium cyanide (11.1 g, 41.4 mmol) was added. The mixture was heated at 65° C. for 3 hours and then cooled to room temperature and extracted with ethyl ether (100 mL). The organic layer was washed with saturated NaHCO3 (2×50 mL), dried over MgSO4, and concentrated under reduced pressure to give (S)-1-benzyl-3-cyanopyrrolidine (3.1 g, 85%) as a yellow oil: VPC: 100%; 1HNMR (CDCl3, 60 MHz): δ1.9-2.4 (m, 2H), 2.5-3.1 (m, 5H), 3.60 (s, 2H), 7.30 (s, 5H).
Reaction SMILES: O[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[N:7]=[C:6]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[CH:18][CH:17]=2)[C:5](=[O:27])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1COCC1>[C:21]1([N:20]2[C:16]([C:6]3[C:5](=[O:27])[CH:4]=[C:3]4[CH2:2][O:15][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[N:8]4[N:7]=3)=[CH:17][CH:18]=[N:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1cc(CO)n(-c2ccccc2O)nc1-c1ccnn1-c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1cc2n(nc1-c1ccnn1-c1ccccc1)-c1ccccc1OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
6-(Hydroxymethyl)-1-(2-hydroxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (190 mg) was dissolved in toluene (2 mL) and THF (3 mL), triphenylphosphine (202 mg) and 1.9M DIAD toluene solution (410 μL) were added at 0° C., and the reaction mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (130 mg).
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[NH2:20][C:21]([NH2:23])=[O:22].[O-]CC.[Na+]>[Pd].C(O)C>[O:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([NH:20][C:21]([NH2:23])=[O:22])=[O:19])=[CH:11][CH:10]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CCc1ccc(Oc2ccccc2)cc1
Reactant: NC(N)=O
Agent: [Pd]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)NC(=O)CCc1ccc(Oc2ccccc2)cc1

Procedure:
4-phenoxy-benzaldehyde was reacted with triethyl phosphonoacetate to yield 3-(4-phenoxyphenyl)-acrylic acid ethyl ester, which was then reduced with H2 using palladium-on-carbon catalyst to yield 3-(4-phenoxyphenyl)-propionic acid methyl ester (19). Urea (1.20 g, 19.99 mmol) was dissolved in sodium ethoxide (2 M, 6.7 mL, 13.4 mmol) at 80° C. under argon, and to this a solution of 19 (1.71 g, 6.67 mmol) in anhydrous ethanol (8 mL) was added and heated at this temperature for 1 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by 5% aqueous HCl and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (1:1) containing acetic acid (1%) followed by recrystallization from ethanol. Yield: 113 mg, 5.6%.