Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:5][CH:4]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.CCN(P1(N(CC2C=CC=CC=2)CCCN1C)=NC(C)(C)C)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C1COCC1>[C:28]1([CH2:34][C:35]([NH:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][C:11]4[CH:10]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:4][CH:5]=5)[N:14]=[CH:13][N:12]=4)[C:21]=3[N:22]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1Cc1ccccc1
Solvent: C1CCOC1
Solvent: C=Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1

Procedure:
According to the procedure described in Example 67, the title compound was prepared by using 4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 65), (0.19 g, 0.5 mmol), phenylacetyl chloride (0.13 mL, 1 mmol, Aldrich), and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, polymer bound (BEMP resin) (0.34 g, 0.75 mmol) in THF (5 mL). Purification by silica gel chromatography (1:4 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 507 (M+1). Mp: 188.6–191.0° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[I-].[CH3:20][N+]1C=CC=CC=1.[BH4-].[Na+]>>[C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH2:12][N:13]([CH3:20])[CH2:14][CH2:15][CH:16]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCc1ccccc1)c1cccnc1
Reactant: C[n+]1ccccc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CI
Product: CN1CCC=C(C(=O)CCc2ccccc2)C1

Procedure:
Employing the general methods of Examples 4 and 6 above, 10 g (47.3 mmol) of 3-phenyl-1-(3-pyridinyl)-1-propanone were first converted by the action of methyl iodide to the N-methylpyridinium iodide and then reduced by the action of sodium borohydride to produce 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone which was isolated as the hydrochloride salt (5.2 g, 58%), mp 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][SiH:19]([CH3:21])[Cl:20]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Si:19]([CH3:21])([CH3:18])[Cl:20])=[CH:4][C:3]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[SiH](C)Cl
Reactant: C=CCc1ccc(F)c(Oc2ccccc2)c1
Solvent: C1CCOC1
Product: C[Si](C)(Cl)CCCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4.1 g (0.018 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propene and 0.060 g (0.00015 mole) of hydrogen hexachloroplatinate hydrate in 15 mL of tetrahydrofuran was added slowly 2.0 g (0.021 mole) of dimethylchlorosilane. Upon completion of addition the reaction mixture was stirred overnight and then was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]O)=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=3)=[N:6]2)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:24].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:24][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([F:22])[CH:15]=2)[CH:8]=1
Reactant: COc1ccc(-c2cc(CO)c(=O)n(CC3CC3)n2)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reaction time: 1 h
Yield: 69.2 %

Procedure:
2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one (185 mg, 0.61 mmol), carbon tetrabromide (404 mg, 1.2 mmol) and pyridine (48 mg, 0.61 mmol) were dissolved in tetrahydrofuran (3 mL), and under ice-cold stirring, a solution of triphenylphosphine (319 mg, 1.2 mmol) in tetrahydrofuran (3 mL) was added. Under ice cooling, the mixture was stirred for 1 hour, and further stirred at room temperature. Insoluble materials were filtered off, the solvent was distilled off under reduced pressure, and the residue was isolated and purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to yield the title compound as a yellow powder (yield: 155 mg, 69.5%).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=2[Cl:16])[CH:2]=1.[CH3:18][CH:19]1[CH2:25][C:24](=[O:26])[O:23][C:21](=[O:22])[CH2:20]1.C(N(CC)CC)C>CCOCC>[C:21]([CH2:20][CH:19]([CH3:18])[CH2:25][C:24]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:17])=[CH:14][C:15]=1[Cl:16])=[O:26])([OH:23])=[O:22]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CC1CC(=O)OC(=O)C1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CC(=O)O)CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reaction time: 20 h
Yield: 23 %

Procedure:
A mixture of triclosan (22.3 g.), 3-methylglutaric anhydride (15.0 g.) and triethylamine (15 ml.) in ether (250 ml.) was stirred for 20 hours, and then washed first with 2M hydrochloric acid (50 ml.) and then with water (3×150 ml.). The ether phase was dried (MgSO4) and evaporated. A portion (20 g.) of the residual oil was purified by chromatography on silica gel using methylene chloride as eluant to give (D) as a colourless oil (7.4 g.) ; NMR (CDCl3): 0.8-1.3 (3H,d, CH3), 2.1-2.8 (5H,m,CH2CO+CH3CH), 6.7-7.6 (6H, m, aromatic H), 11.25 (1H,s, CO2H)ppm.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cc(OC)cc(OCCCCCCl)c1
Agent: Cl
Product: COc1cc(OC)cc(OCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound and 5-(3,5-dimethoxyphenoxy)pentyl chloride (1.4 g) were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(3,5-dimethoxyphenoxy)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[F:15][C:16]1[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:23][CH:22]=[C:21]([F:32])[C:17]=1[C:18](Cl)=[O:19].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:18]([C:17]3[C:16]([F:15])=[C:24]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=3[F:32])=[O:19])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Cl)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To aluminum trichloride (8.89 g, 66.7 mmol) was added methylene chloride (150 mL) under an atmosphere of nitrogen below 5° C. Into this, 5-bromo-7-azaindole (67, 1.64 g, 8.34 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 60.0 minutes and 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl chloride (46, 3.50 g, 11.8 mmol) in methylene chloride (20 mL) was added. The reaction was stirred for 6 hours and warmed to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated. The desired compound was isolated by silica gel column chromatography (methylene chloride/methanol 5%) to give a white solid (P-0773, 1.2 g, 31.4%). MS (ESI) [M+H+]+=460.0, 462.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:27])([CH3:26])[CH2:22][NH:23]4)=[CH:19][CH:18]=3)[C:10]2=[O:28])[CH:5]=[CH:4][N:3]=1.[N:29]([CH:32]1[CH2:37][CH2:36][N:35](C(=O)C(F)(F)F)[CH2:34][CH2:33]1)=[C:30]=[O:31]>C1COCC1>[NH:35]1[CH2:36][CH2:37][CH:32]([NH:29][C:30]([N:23]2[C:24]3[C:20](=[CH:19][CH:18]=[C:17]([N:11]4[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=5)[C:10]4=[O:28])[CH:25]=3)[C:21]([CH3:27])([CH3:26])[CH2:22]2)=[O:31])[CH2:33][CH2:34]1
Reactant: O=C=NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc(N)n4)C(C)(C)C3=O)ccc21
Solvent: C1CCOC1
Product: CC1(C)CN(C(=O)NC2CCNCC2)c2cc(N3C(=O)N(Cc4ccnc(N)n4)C(C)(C)C3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
200 mg (0.53 mmol) of 1-(2-aminopyrimidin-4-ylmethyl)-3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethylimidazolidine-2,4-dione were dissolved in 3 ml of THF, and a solution of 118 mg (0.53 mmol) of 4-isocyanatotrifluoroacetylpiperidine in 3 ml of THF was added. After stirring at RT for 1 h, the mixture is concentrated and taken up in 3 ml of dioxane and 3 ml of 2 N HCl, and the mixture is heated in a microwave at 120° C. for 15 min. For workup, the mixture was concentrated and the remaining residue was purified by means of preparative HPLC (RP18, acetonitrile/water, 0.1% TFA). After release of the base by treating with sodium hydrogencarbonate solution, 60 mg of the title compound were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCC1CO1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.1 %

Procedure:
Quinoline-6-carboxylic acid (1 g; 5.78 mmol) is dissolved in DMF (10 mL) at ambient temperature. Epichlorohydrin (0.4517 mL; 5.59 mmol) is added followed by mortar ground potassium carbonate (0.80 g; 5.79 mmol). The mixture is stirred at ambient temperature for 48 hours. Potassium iodide (96 mg; 0.58 mmol) is added and stirring is continued at ambient temperature for 24 hours. The mixture is heated to 60° C. and maintained for 72 hours. After cooling, the mixture is poured onto water (700 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts are washed successively with water (100 mL), and brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo at 30C. The residue is purified via silica gel chromatography with gradient elution (20%→67% ethyl acetate in hexanes) affording the desired product (270 mg) as a white solid. ESMS: MH+ 230.0 (base).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[CH2:33]([NH:40][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][O:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COC1CCCCO1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO[C@@H]1CCCCO1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold solution (5° C.) of 10.00 g of Intermediate 2 in 150 mL of dichloromethane was added 5.89 g (0.036 mol) of 1,1′-carbonyldiimidazole. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. Then, it was cooled to 5° C. and 4.37 g (0.041 mol) of benzylamine was added dropwise and the reaction was stirred at room temperature overnight. The organic phase was washed with 1 M HCl (2×80 mL), sodium bicarbonate solution (2×80 mL), water (80 mL), brine (80 mL) and dried over sodium sulfate. The solvent was evaporated under vacuum yielding 14.36 g as an oil. The oil was not purified and used directly in the following step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]1([CH2:31][C:32]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[CH:38]([C:44]([O:46][CH:47]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[C:39]([CH:42]=O)=[CH:40][S:41][C@H:36]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.[Zn].C(OCC)(=O)C>[C:25]1([CH2:31][C:32]([NH:34][CH:35]2[C:60](=[O:61])[N:37]3[CH:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)=[O:45])[C:39]([CH:42]=[C:20]([Br:24])[Br:21])=[CH:40][S:41][C@H:36]23)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Br)Br)=CS[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a stirred mixture of triphenylphosphine (40.7 g) and zinc powder (18.5 g) in methylene chloride (250 ml) was added carbontetrabromide (45 g) at 20°-30° C. Benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4-carboxylate (10 g) was added portionwise to the above reaction mixture, and the mixture was stirred for 30 minutes at room temperature. Triphenylphosphine oxide was solidified by addition of ethyl acetate to the reaction mixture and removed by filtration. The residue left by removal of the solvents was chromatographed on silica gel. The elution with chloroform containing ethyl acetate (10%) gave benzhydryl 7-phenylacetamido-3-(2,2-dibromovinyl)-2-cephem-4-carboxylate (4.4 g).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[C:28]([CH2:30][C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[N:10]=[CH:11][CH:12]=[C:7]4[CH2:6][CH2:5][O:4][C:8]=34)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32])#[N:29]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (41 mg, 65%), MS (ISP) m/z=398.3 [(M+H)+], mp 215.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-cyano-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27](O)=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:30])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.Cl.Cl.[NH:52]1[CH2:56][CH2:55][N:54]=[C:53]1[C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][NH2:65])=[CH:59][CH:58]=1>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:65][CH2:64][CH2:63][C:60]3[CH:61]=[CH:62][C:57]([C:53]4[NH:54][CH2:55][CH2:56][N:52]=4)=[CH:58][CH:59]=3)=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:30])[CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 251.9 %

Procedure:
A solution of [5-(3,4-dichloro-benzenesulfonyl)-8-fluoro-5,6-dihydro-phenanthridin-6-yl]-acetic acid (210 mg, 0.45 mmol), triethylamine (0.07 mL, 1.5 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.19 g, 0.5 mmol) in dry dimethyl formamide (5 mL) was stirred at room temperature for five minutes before 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) (131 mg, 0.5 mmol) was added. The pH of the reaction mixture was adjusted to 8 by addition of triethylamine, the so obtained mixture was stirred at room temperature overnight, then concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol:NH4OH=5:1:0.1) to yield 382 mg (75%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25](O)=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[N-:28]1C=CN=C1.N.O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[C:17]3[CH:18]=[C:19]4[O:24][CH2:23][O:22][C:20]4=[CH:21][C:16]=3[CH2:15][C:14]([C:25]([NH2:28])=[O:26])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(C2=NN=C(C(=O)O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reactant: c1c[n-]cn1
Agent: N
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NN=C(C(N)=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
4.17 g (10.0 millimoles) of 5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine-8-carboxylic acid-imidazolide are suspended in a mixture of 85 ml dichloro methane and 15 ml of a 15% aqueous methanolic ammonia solution. The reaction mixture is sealed and stirred at room temperature for 6 hours. The mixture is cooled with icecold water. The precipitated product is filtered and washed with 20 ml of diethyl ether. Thus 3.11 g of the desired compound are obtained, yield 85%, mp.: 266–268° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]#[N:17])[CH2:12][CH2:11]1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:18]([O:22][C:23](=[O:24])[NH:25][C@H:26]([C:27](=[O:28])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]#[N:17])[CH2:14][CH2:15]1)[CH3:30])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#C[C@H]1CC[C@H](Nc2cc(F)ccc2N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CC[C@H](C#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of trans-4-(2-amino-5-fluorophenylamino)cyclohexanecarbonitrile (195 mg, 0.83 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (174 mg, 0.92 mmol), HOAt (125 mg, 0.92 mmol), 4-methylmorpholine (0.20 mL, 1.83 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (192 mg, 1.0 mmol) in THF (3 mL) was stirred at RT for 18 h under a nitrogen atmosphere. The reaction mixture was partitioned between EtOAc and water. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a white foam (199 mg, 60%). LCMS (Method B): RT 3.37 [M+H]+ 405.2
Reaction SMILES: [NH2:1][OH:2].C1COCC1.C[O:9][C:10](=O)[CH:11]([N:16]([CH3:31])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])[C:12]([NH:14][CH3:15])=[O:13]>C(O)C>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([C:17]([N:16]([CH3:31])[CH:11]([C:12]([NH:14][CH3:15])=[O:13])[C:10]([NH:1][OH:2])=[O:9])=[O:18])=[CH:24][CH:23]=1
Reactant: NO
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)C(C(=O)NO)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A 50% aqueous solution (0.20 mL) of hydroxylamine was added to a THF (0.25 mL)-ethanol (0.20 mL) solution of 4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (30 mg) as obtained in Example 1-(1), and the mixture was stirred for 4 hours at room temperature. The solvents were distilled off under reduced pressure, and the resulting residue was purified by preparative silica gel thin-layer chromatography (chloroform/methanol=8/1). Upon addition of IPE, the precipitated solid was separated by filtration, and dried to obtain 2-[(biphenyl-4-ylcarbonyl)(methyl)amino]-N-hydroxy-N′-methylpropanediamide (Compound 1, light yellow solid) (17 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[C:17]([NH:27][N:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[N:16]=1>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[C:17]([NH:27][N:28]=[CH:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=3)[N:16]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(C=NNc2cc(-c3ccccc3)nc(Cl)n2)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(F)(F)Oc1ccc(C=NNc2cc(-c3ccccc3)nc(Nc3ccc(Cl)cc3)n2)cc1

Procedure:
To a −78° C. THF solution of 4-chloroaniline was added 1 equivalent of nBuLi to prepare the lithium anilide. The solution was allowed to come to room temperature under nitrogen atmosphere. Aliquots of the lithium anilide were added portion wise to a THF solution of 2-chloro-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidine (XX) containing 0.05 equivalents (relative to (XX)) of Bis(triphenylphosphine) palladium(II) dichloride. The reaction was followed by thin layer chromatography. When the starting material XX was consumed the reaction was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered and concentrated at reduced pressure. The product, N-(4-chlorophenyl)-4-phenyl-6-(2-(4-(trifluoromethoxy)benzylidene)hydrazinyl)pyrimidin-2-amine (Example 58) was obtained as a solid. ESI/MS 483.9728, 485.9988 (M+H).