Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].N.CO.Cl.C([N:41]=C=NCCCN)C.ON1C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:34])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([NH2:41])=[O:31])=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCN=C=NCCCN
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(N)=O)c(F)c3)c2)c(C)c1
Yield: 88.7 %

Procedure:
A solution of 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoic acid (0.251 g, 0.500 mmol), 7 M ammonia/methanol (0.4 mL, 2.80 mmol) solution, 1-ethyl-3-(3-aminopropyl)carbodiimide hydrochloride (288 g, 1.50 mmol), 1-hydroxybenzotriazole (0.230 g, 1.50 mmol), 1,8-diazabicyclo[5.4.0]-7-undecene (0.448 mL, 3.00 mmol) and triethylamine (0.502 mL, 3.60 mmol) in acetonitrile (3 mL) was stirred at room temperature for 24 hr. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) to give the title compound (0.206 g, yield 89%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccccc2c1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2c1Br
Temperature: 25 °C
Yield: 42.7 %

Procedure:
1-Bromo-2-methyl naphthalene (25 g), N-bromosuccinimide (24.2 g), carbon tetrachloride (250 mL) and a catalytic amount of azo(bis)isobutylnitrile were refluxed 40 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and volatile materials were removed in vacuo on a rotary evaporator. the residue was treated with hot hexane (steam bath, about 2×250 mL). The hexane solution was decanted and cooled in ice. The product was collected on a Buchner funnel and air dried to give 14.5 g of 1-bromo-2-bromomethylnaphthalene as white crystals.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:18][CH:17]=1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:21]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCCCOc1ccc(C(=O)Nc2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 55.2 %

Procedure:
In a manner similar to that described in Example 3, 4-butoxy-benzoyl chloride (0.073 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.051 g of 4-[4-(4-butoxy-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+370.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.N([O-])=O.[Na+].[N-:33]=[N+:34]=[N-].[Na+]>C(O)C>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:10][C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 41.9 %

Procedure:
Methyl 3-amino-2,6-bis(4-methoxyphenyl)isonicotinate (234 mg, 0.642 mmol) was dissolved with heating in ethanol (8 mL). After cooling to room temperature, 17% aqueous HCl (4 mL) was added and the reaction was cooled in an ice bath. Sodium nitrite (70.9 mg, 1.027 mmol) was added and the solution turned orange-red. After 25 min, sodium azide (66.8 mg, 1.027 mmol) was added and, after a further 20 min, the reaction was removed from the bath and left stirring at room temperature for 1 hr. The reaction was partitioned between ethyl acetate and sufficient saturated aqueous sodium bicarbonate solution to neutralize the acid. The organic phase was separated, washed with brine, and dried with sodium sulfate. Radial silica gel chromatography (step gradient elution with hexane containing 5 to 20% ethyl acetate) afforded methyl 3-azido-2,6-bis(4-methoxyphenyl)isonicotinate (105 mg, 42% yield) as a yellow solid. MS (ESI) m/z 391.1 (M+H). 1H NMR (CDCl3) δ ppm 8.03 (2H, d, J=8.85 Hz), 7.93 (1H, s), 7.83 (2H, d, J=8.85 Hz), 7.02 (2H, d, J=8.85 Hz), 6.98 (2H, d, J=9.16 Hz), 4.03 (3H, s), 3.88 (3H, s), 3.86 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32]>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:31][CH3:32]
Reactant: CCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 9.5 h

Procedure:
To a solution of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate (0.300 g) in N,N-dimethylformamide (2.5 mL) was added potassium carbonate (0.194 g). Then 1-bromopropane (0.119 mL) was added, and the resulting mixture was stirred at room temperature for 9.5 hours. Potassium carbonate (0.180 g) and 1-bromopropane (0.110 mL) were added, and stirring was continued at room temperature for additional 14 hours. The reaction mixture was partitioned between diethyl ether (30 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.333 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33].[Cl-].[NH4+]>CCCCCC.C1COCC1>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]([OH:29])[C:13]2([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[CH:26][C:25]=1[N+:32]([O-:34])=[O:33]
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C(O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
9.7 ml (24.3 mmol) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution, cooled to from −20° C. to −30° C., of 3.4 ml (24.3 mmol) of diisopropylamine in 20 ml of abs. THF. After the addition had ended, the mixture was stirred at from −20° C. to −30° C. for another 30 min. The mixture was then cooled to −78° C., and a solution of 2.53 g (17.8 mmol) of tert-butyl cyclopropanecarboxylate in 15 ml of abs. THF was added dropwise at this temperature. After 4 h at −78° C., a solution of 3 g (16.2 mmol) of 4-chloro-3-nitrobenzaldehyde in 15 ml of abs. THF was then added. The reaction mixture was slowly warmed to RT overnight and then allowed to stand at RT for three days, and saturated aqueous ammonium chloride solution was then added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 50:1→20:1). This gave 3.21 g of the target compound (60.6% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][C:12]([CH:14]([OH:31])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:19][CH:18]=3)=[N:11][CH:10]=2)[N:4]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:13][C:12]([C:14](=[O:31])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:19][CH:18]=3)=[N:11][CH:10]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1cccc(-c2cnc(C(O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc(-c2cnc(C(=O)CCc3ccc(COc4ccccc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.1 %

Procedure:
2-Cyano-6-(2-(1-hydroxy-3-(4-(phenoxymethyl)phenyl)propyl)oxazol-5-yl)pyridine (133 mg, 0.323 mmol) was dissolved in anhydrous CH2Cl2 (4 mL) and Dess-Martin periodinane (205 mg, 0.485 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 2.5 h. The addition of saturated aqueous NaHCO3 quenched the reaction and the organic layer was washed with saturated aqueous Na2S2O3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 0-1% MeOH/CH2Cl2) to provide 2-cyano-6-(2-(3-(4-(phenoxymethyl)phenyl)propanoyl)oxazol-5-yl)pyridine as a yellow solid (98 mg, 74%): 1H NMR (CDCl3, 500 MHz) δ 8.04 (dd, 1H, J=8.1, 0.9 Hz), 7.98-7.95 (m, 2H), 7.68 (dd, 1H, J=7.7, 0.9 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.30-7.26 (m, 4H), 6.97-6.94 (m, 3H), 5.03 (s, 2H), 3.74 (t, 2H, J=7.5 Hz), 3.12 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 187.3, 158.7, 157.5, 151.4, 147.8, 140.0, 138.4, 135.1, 134.3, 129.4, 128.5, 128.7, 128.1, 127.8, 123.0, 120.9, 116.5, 114.8, 69.7, 40.7, 29.3; HR ESI-TOF m/z 410.1501 (M+H+, C25H19N3O3, requires 410.1499).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:42]=[CH:41][C:38](C=O)=[CH:37][CH:36]=1.[BH4-].C(OC(=O)C)(=O)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:38]3[CH:41]=[CH:42][C:35]([CH3:34])=[CH:36][CH:37]=3)[CH2:23][CH2:22]2)[C:10](=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [BH4-]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(Cc3ccc(C)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Methylbenzaldehyde (0.134 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 22 mg; HRMS (FAB+, NBA) (M+H)+ 457.2853, C30H37N2O2 requires 457.2855; LC-MS: (M+H)+ 457.2, tr 6.97 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=2)[CH2:4][CH2:3]1>C(O)C.C1CCCCC=1.[Pd]>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9][C:10]=1[NH2:15]
Reactant: Cc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1ccc(N2CCN(C)CC2)cc1N
Temperature: 80 °C

Procedure:
To a solution of 1-methyl-4-(4-methyl-3-nitro-phenyl)-piperazine (9.0 g, 38.29 mmol) in ethanol (100 mL) and cyclohexene (7 ml), Pd/C 10% (1.5 g) was added. The mixture was heated at 80° C. for 6 hours. The Pd was filtered from the reaction and the solvents were removed from the filtrate under reduced pressure. The crude was diluted with DCM and treated with HCl in dioxane; the precipitate was collected and washed with diethyl ether to give the final compound as a brown solid in quantitative yield.
Reaction SMILES: [C:1]1(=[C:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:16]#[N:17].[K+]>>[CH3:14][C:9]1([CH3:13])[O:10][C:11](=[O:12])[CH:6]([C:1]2([C:16]#[N:17])[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:15])[O:8]1
Reactant: CC1(C)OC(=O)C(=C2CCCC2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Product: CC1(C)OC(=O)C(C2(C#N)CCCC2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 5-cyclopentylidene-2,2-dimethyl-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:24]([Cl:25])=[CH:23][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH2:21])[CH:17]=[CH:16][C:15]=3[Cl:22])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:24]([Cl:25])=[CH:23][C:9]2[N:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH:21][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[CH:17]=[CH:16][C:15]=3[Cl:22])[NH:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)c1cc2[nH]c(Nc3cc(CN)ccc3Cl)nc2cc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2[nH]c(Nc3cc(CNC(=O)C(C)(C)C)ccc3Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Ethyl-2-[5-(aminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-carboxylate (1.00 g, 2.4 mmol), pivaloyl chloride (0.296 ml, 2.4 mmol), 1.5 ml TEA and 50 ml THF were stirred for 18 h at rt. The mixture was concentrated, diluted with EtOAc, washed 2× with H2O, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the sub-title compound. Yield 0.92 g (83%).
Reaction SMILES: Cl.[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>>[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH2:27])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)C3CCCC3)ccc21
Yield: 45 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 45% of theory, C25H30N3O4 (462.6) ##EQU48##
Reaction SMILES: ClC1C=CC(C=[N:9][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH2:15][C:16]#[CH:17])[C:11]([O:13][CH3:14])=[O:12])=CC=1.Cl>C(OCC)C.O>[NH2:9][C:10]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH2:15][C:16]#[CH:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: C#CCC(N=Cc1ccc(Cl)cc1)(C(=O)OC)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C#CCC(N)(C(=O)OC)c1ccc(OC)cc1
Yield: 92.6 %

Procedure:
962 mg of the compound prepared in Stage 2 are stirred at AT in 14 mL of ethyl ether and 3.5 mL of 1 N hydrochloric acid for 18 hours. The mixture is diluted with water and the product is extracted with ethyl acetate. The solvent is dried over magnesium sulphate and evaporated to produce 584 mg of product, in the form of colourless oil (Yd=92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([C:29]2[S:33][C:32]([C:34]([NH:36][NH2:37])=[O:35])=[CH:31][CH:30]=2)=[O:28])[CH2:23][CH2:22]1)([CH3:20])[CH3:19].Cl.O1CCOCC1.CN(C)C=O>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:37][NH:36][C:34]([C:32]3[S:33][C:29]([C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH:18]([CH3:20])[CH3:19])[CH2:26][CH2:25]4)=[O:28])=[CH:30][CH:31]=3)=[O:35])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)N1CCN(C(=O)c2ccc(C(=O)NN)s2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)N2CCN(C(C)C)CC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 54 %

Procedure:
28 mg of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO2004/108683) and 29.7 mg of 5-(4-isopropylpiperazine-1-carbonyl)thiophene-2-carbohydrazide prepared in Reference Synthetic Example 1 in 2 mL of isopropyl alcohol were heated with 3 mg of p-tosylic acid monohydrate and 25 μL (1 eq) of 4 M hydrogen chloride/dioxane at 105° C. for 8 hours. The reaction solution was further heated with 2 mL of dimethylformamide at 105° C. for 5 hours and cooled to room temperature. The precipitated solid was recovered by filtration and washed with 1 mL of isopropyl alcohol and 1 mL of chloroform, and the resulting crystals were dried to give the desired product (yield 54%).
Reaction SMILES: C(OO)(=[O:3])C.C([O-])(=O)C.[Na+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1[CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23].C([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)Cl>[CH3:11][C:12]12[O:3][C:13]1([CH:20]([OH:24])[CH2:21][CH:22]=[CH2:23])[C:14]([CH3:18])([CH3:19])[CH2:15][CH2:16][CH2:17]2
Reactant: CC(=O)OO
Reactant: C=CCC(O)C1=C(C)CCCC1(C)C
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCC(O)C12OC1(C)CCCC2(C)C

Procedure:
A mixture of 40 % peracetic acid (105 g.) and anhydrous sodium acetate (3.0 g.) was added at 25° with stirring to a suspension of 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (97g.) and anhyd. sodium acetate (60 g.) in 175 ml. of CH2Cl2 (1.5 h.). Stirring was continued for one night and 500 ml. of water were then added to the reaction mixture. The organic layer was separated and, after the usual treatments, distilled to give 98 g. (83 %) of two diastereoisomers of the epoxy product. V.p.c. enabled the separation of the two isomers (Carbowax, 170°, 3 m)
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.O1[CH2:30][CH2:29][O:28][CH2:27]C1>O>[C:4]1(=[O:19])[N:5]([CH:6]2[C:17](=[O:18])[N:8]3[C:9]([C:14]([O:16][CH2:3][C:2]4[CH:1]=[CH:30][C:29]([O:28][CH3:27])=[CH:22][CH:23]=4)=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:1](=[O:24])[C:2]2=[CH:23][CH:22]=[CH:21][CH:20]=[C:3]12
Reactant: C1COCCO1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Solvent: O
Product: COc1ccc(COC(=O)C2=C(C)CS[C@@H]3C(N4C(=O)c5ccccc5C4=O)C(=O)N23)cc1
Reaction time: 2 h

Procedure:
To a suspension of 13.4 g. (38 mmol.) of 7-phthalimido-3-methyl-3-cephem-4-carboxylic acid in 20 ml. of dioxane and 10 ml. of water were slowly added 3.8 g. of KHCO3. The solution was evaporated to dryness, and 100 ml. of DMF and 8.8 g. of p-methoxybenzyl bromide were added to the potassium salt residue. The mixture was stirred for 2 hrs. and then poured onto 200 g. of ice. The resulting mixture was extracted twice with ethyl acetate. The extract was washed with water and brine, dried, and the solvent was then evaporated. The residue was recrystallized from ethyl acetate. Yield: 4.1 g. of large crystals, m.p. 118°-121°; second crop 1.8 g.; [α]D + 41.2° (MeCN), ir (CHCl3) 1800, 1785, 1745 and 1735 cm-1, nmr (CDCl3) δ 2.15 (s, 3, CH3); 3.0 and 3.7 (ABq, 2, J = 15 Hz), 3.8 (s, 3, CH3), 5.11 (d, 1, J = 4.5 Hz), 5.28 (s, 2, CH2), 5.75 (d, 1, J = 4.5 Hz), 6.8- 7.8 (m, 8).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:29]#[N:30])=[N:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])=[C:16]([C:25]([F:28])([F:27])[F:26])[CH:15]=2)=[CH:10][C:11]=1[NH:12][CH3:13]>O.Cl.CN1C(=O)CCC1.C(OCC)(=O)C>[OH:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[N:8]=[C:7]([C:29]#[N:30])[C:6]3[N:5]=[N:1][N:12]([CH3:13])[C:11]=3[CH:10]=2)=[CH:15][C:16]=1[C:25]([F:28])([F:26])[F:27]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCCO)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCCO)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A solution of sodium nitrite (13.07 g) in water (40 ml) was added to 3-amino-6-(4-(3-hydroxypropoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (49.6 g) in 2M hydrochloric acid (203 ml) and NMP (180 ml). The mixture was stirred at room temperature for 2 hours then diluted with ethyl acetate (50 mml), and the mixture washed with water (300 ml+100 ml×4), the organic layer was dried over magnesium sulphate, solvent removed under reduced pressure. The residue was then columned on silica gel using DCM then DCM-MeOH (199:1) as eluant to give expected product (10.34 g). 1H NMR (CD3OD) δ: 8.55 (s, 1H), 8.39-8.45 (m, 2H), 7.35 (d, 1H), 4.45 (s, 3H), 4.30 (t, 2H), 3.80 (t, 2H), 2.06 (quin, 2H). MS m/z 378 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=S)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCCO)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: NCc1cccnc1
Reactant: S=C1Nc2ccc(Cl)cc2Nc2ccccc21
Solvent: CCOCCO
Product: Clc1ccc2c(c1)Nc1ccccc1C(NCc1cccnc1)=N2
Yield: 59 %

Procedure:
A solution of 0.41 g (1.57 mmol) of 7-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL 2-ethoxyethanol was treated with 0.32 mL (3.14 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 22 hours. The solvent was removed under reduced pressure and the residue mixed with EtOAc and filtered to give 0.31 g of product. The filtrate was concentrated and chromatographed on silica gel, eluting with EtOAc to give an additional 0.16 g of product. The material was combined and recrystallized from EtOAc/hexane to give 0.3 g (56.6% yield) of the product as a pale yellow solid, mp 218-220° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =335.