Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([O:25]CC4C=CC=CC=4)=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:3]1.C1COCC1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 12 h

Procedure:
A solution of 2.50 g (4.38 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 50 mL DCM was combined with 250 mg 10% Pd/C and hydrogenated at RT under a hydrogen pressure of 3000 hP for 4.5 h. To complete the reaction a further 250 mg catalyst were added, the mixture was hydrogenated for 12 h at 40° C., combined with 25 mL THF and 250 mg catalyst and hydrogenated for a further 12 h at 40° C. The catalyst was suction filtered and the filtrate was evaporated down i.vac. The residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH2:19])[N:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:19][C:5](=[O:7])[CH3:6])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N)cc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc2ccccc2c(C)n1
Reaction time: 3.5 h

Procedure:
Acetic anhydride (1.4 mL, 15 mmol) was added to a suspension of Example 141A (0.79 g, 5.0 mmol) and triethylamine (0.76 ml, 5.5 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred for 3.5 hours, then the volatiles were removed under reduced pressure. The residue was chased with toluene (3×25 mL) and then concentrated under reduced pressure to provide the title compound. MS (ESI) m/z 201 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].P(Br)(Br)[Br:18].O>CCOCC>[Br:18][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccccc1CCCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)Cc1ccccc1CCCBr

Procedure:
To a solution of ethyl [2-(3-hydroxypropyl)-phenyl]acetate (44.4 g., 0.20 mole) in ether (300 ml.) is added dropwise during 40 minutes a solution of phosphorus tribromide (20.7 g., 0.075 mole) in ether (100 ml.). The temperature is maintained at 25°-28° C. during this time by means of a cold water bath. The reaction solution is then heated a reflux for 4 hours. It is cooled and poured into iced-water. The ether layer is separated, washed with water, dried over magnesium sulfate, and evaporated in vacuo to yield ethyl [2-(3-Bromopropyl)phenyl]acetate.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([I:15])[CH:9]=1)(=[O:5])=[O:4].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].C(O)(C)C>CO>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([I:15])[CH:9]=1)(=[O:5])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: CNS(=O)(=O)CCc1ccc(N)c(I)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CNS(=O)(=O)CCc1ccc(NCc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-(4-amino-3-iodo-phenyl)-ethanesulfonic acid methylamide (100 g) in anhydrous methanol (500 ml), a solution of benzaldehyde (46 g) in methanol (100 ml) was added dropwise maintaining temperature below 30° C. The reaction mass was stirred for 2-3 hours at 25° C. and sodium borohydride (12 g) was added over a period of 2 hours maintaining the temperature below 30° C. The reaction mass was stirred for about 2 hours at 25° C. Methanol was evaporated from the mixture and water (1000 ml) was added. The solution was extracted with dichloromethane (2000 ml). The organic layer was washed with water and distilled under vacuum to obtain a solid. The solid was treated with isopropyl alcohol (500 ml), filtered and dried under vacuum at 50-55° C. to obtain the title compound. (Yield: 116 g, HPLC Purity: 99%)
Reaction SMILES: [K].[CH:2]1([OH:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:12]I>O>[CH3:12][O:8][CH:5]1[CH2:6][CH2:7][CH:2]([OH:9])[CH2:3][CH2:4]1
Reactant: CI
Reactant: OC1CCC(O)CC1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Product: COC1CCC(O)CC1

Procedure:
To mono-potassium salt of 1,4-cyclohexanediol which had been prepared from 17.5 g of 1,4-cyclohexanediol and 9.3 g of potassium hydroxide, 32 g of methyl iodide was added, and the resultant mixture was heated under reflux for 5 hours. After the reaction was completed, water was added and then the mixture was extracted with chloroform. The extract was subjected to distillation under reduced pressure to obtain 10.34 g of 4-methoxycyclohexanol. b15 : 100°-103° C.
Reaction SMILES: Cl.[N:2]1([CH:7]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][N:4]=[CH:3]1.Cl.[CH3:21]O>>[CH3:21][O:16][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][C:11]([CH:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[CH2:8][CH2:9][CH3:10])=[CH:12][CH:13]=1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Reactant: CO
Agent: Cl
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccnc1

Procedure:
1.0 of 4-[1-(1-imidazolyl)-butyl]-benzoic acid, hydrochloride (of example 2) is dissolved in 30 ml of methanol, hydrochloric-acid gas is introduced for 10 minutes, refluxed for 30 minutes and concentrated by evaporation. The residue is distilled on a bulb tube, boiling point 190° C./0.03 mbar. 0.55 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid methyl ester is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([N:11]=1)=[CH:9][NH:8][C:7](=O)[N:6]=2.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[N:8]=[CH:9][C:10]2[N:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:6]=1
Reactant: O=c1nc2ccc(Cl)nc2c[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)ncc2n1
Temperature: 0 °C

Procedure:
6-chloro-3H-pyrido[3,2-d]pyrimidin-2-one (3.4 g, 5.2 mmol) are taken up in POCl3 (55 mL) and the mixture is heated for 3 h to 105° C. Then the reaction mixture is added dropwise to ice water, extracted with DCM, the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and 2,6-dichloro-pyrido[3,2-d]pyrimidine (HPLC-MS: MS(M+H)+=200; method AFEC) is obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.[OH:14]O>C1C=CC=CC=1>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1)=[O:14]
Reactant: OO
Reactant: CSc1ccc(-n2cnnn2)cc1
Solvent: c1ccccc1
Product: CS(=O)c1ccc(-n2cnnn2)cc1

Procedure:
1-[p-(Methylthio)phenyl]-1H-tetrazole (2 g.) and 0.9 ml. of 30% hydrogen peroxide were refluxed with stirring in benzene for 3 hours. The benzene was decanted and the precipitate washed with benzene and recrystallized from acetone, m.p. 175°-176° C.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[O:1]=[C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([Cl:18])=[O:8]
Reactant: O=C(O)CCCCC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)CCCCC(=O)c1ccccc1

Procedure:
6-Oxo-6-phenyl hexanoic acid (10.3g; 50 mmole), thionyl chloride (25 ml) and dry benzene (150 ml) were heated under reflux for 3 hours. The reagent and solvent were removed on the rotary evaporator. A further 100 ml of benzene was added and the solution again evaporated under reduced pressure (to remove last traces of thionyl chloride). The quantitatively formed, analytically pure brown solid (mp 53°-6°) was used directly in the Friedel-Crafts acylation of step (b).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[CH2:24]([NH:26][CH3:27])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:26]([CH2:24][CH3:25])[CH3:27])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCNC
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Product: CCN(C)c1nc2c(C)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and ethyl-methyl-amine. Yellow foam. MS (ESI): 355.1 (M+H)+.
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[N+:5]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:9]=[C:10]([S:14]([O:3][CH2:2][C:1]#[N:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: N#CCO
Product: N#CCOS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Preparation: The technique of Example 2 is used to react glycolonitrile with m-nitrobenzenesulfonyl chloride. The product is recovered from the reaction mixture by filtration and recrystallized from ethanol. The dried product (45% conversion) is an amber solid, m.p. 66°-69° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: Cc1ccc(N=C=S)cc1
Reactant: NCc1ccccc1N
Product: Cc1ccc(NC2=Nc3ccccc3CN2)cc1

Procedure:
The title compound (MS: m/e=238.3 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 4-methylphenylisothiocyanate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][OH:30]>CN1C(=O)CCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][CH2:28][CH2:29][OH:30])[CH:3]=1)=[O:15]
Reactant: NCCO
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCO)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1.5 h
Yield: 63 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and 2-aminoethanol (1 ml) in NMP (2 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 130° C. for 1 h and then at 140° C. for 90 min. The mixture was evaporated under vacuum and the residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated yellow oil was treated with EtOAc, sonicated, and treated with hexanes. The solids were filtered, dissolved in DMF (1 mL), and a few drops of water were added. The solution was allowed to stand at room temperature overnight, and then sonicated. The filtered solid was washed with Hexanes/EtOAc (1:1), and then dried to afford the title compound (55 mg, 63%) as a light yellow solid. LCMS E-S (M+H)=399.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1 H) 8.44 (br. s., 1 H) 7.84 (s, 1 H) 7.20 (br. s., 1 H) 6.68 (s, 1 H) 5.89 (s, 1 H) 4.95 (dt, J=13.01, 6.38 Hz, 1 H) 4.72 (t, J=4.93 Hz, 1 H) 4.32 (d, J=4.80 Hz, 2 H) 3.58 (d, J=5.56 Hz, 2 H) 3.38-3.46 (m, 2 H) 2.21 (s, 3 H) 2.12 (s, 3 H) 1.43 (d, J=6.57 Hz, 6 H)
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: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N
Reactant: [N-]=[N+]=[N-]
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: [CH:1]([Li])=[CH2:2].[O:4]1[CH2:9][CH2:8][CH:7]=[CH:6][C:5]1=[O:10]>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]([CH:7]1[CH2:8][CH2:9][O:4][C:5](=[O:10])[CH2:6]1)=[CH2:2]
Reactant: O=C1C=CCCO1
Reactant: [Li]C=C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC1CCOC(=O)C1
Reaction time: 0.25 h

Procedure:
A stream of nitrogen gas is passed through a mixture of 19.6 mL (41.2 mmol) of 2.1M vinyllithium in tetra-hydrofuran and 21 mL toluene to evaporate tetrahydrofuran. The resulting pale yellow suspension is diluted with 21 mL ether and cooled to -78°. To this solution is added 1.87 g (20.9 mmol) cuprous cyanide and the reaction mixture is then warmed to 0° for 2 minutes. The resulting gray suspension is cooled to -78° and 0.9 mL (10.4 mmol) of 5,6-dihydro-2H-pyran-2-one is added. The reaction mixture is stirred at -78° for 30 minutes and at -20° for 15 minutes. The reaction is quenched by the addition of saturated aqueous ammonium chloride and stirred for 1 hour at room temperature. The insoluble salts are filtered off and washed with water (1×20 mL) and ether (2×20 mL). The layers are separated and the aqueous phase is extracted with ether (2×30 mL). Combined organic extracts are dried (MgSO4), filtered and evaporated to give yellow oil which is purified by flash chromatography to obtain 4-ethenyltetrahydro-2H-pyran-2-one as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([C@H:12]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1

Procedure:
trans-Methyl 4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexanecarboxylate (29.00 g, 93.02 mmol) was dissolved in anhydrous acetonitrile (930 mL) and anhydrous DMF (9 mL) and heated at 55° C. under nitrogen for 3 h. The reaction mixture was concentrated in vacuo, then, the solid residue was taken up in DCM, then, basified to pH 10 with 2M ammonia in isopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM, then, loaded onto TEA-basified silica gel. The crude product was purified by a silica gel column chromatography (eluted with 2:3 EtOAc/DCM) to obtain the title compound as a yellow powder; 1H NMR (CDCl3, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85 (ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H), 2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (tt, J=12.4, 3.6 Hz, 1H), 2.96 (tt, J=11.6, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86) [MH+]. HPLC: tR=2.85 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([N:5]([CH3:16])[C:6](=[O:15])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]O)[CH2:2][CH2:3][CH3:4].[Br:17]CC(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH3:16])=[O:15]
Reactant: BrCC(Br)(Br)Br
Reactant: CCCCN(C)C(=O)COCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCN(C)C(=O)COCCCCCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7.2 g of the product of Step C in 73 ml of methylene chloride, there were added at -10° C. 13 g of reaction tetrabromoethane and 10.3 g of triphenylphosphine and the reaction medium was stirred for one hour at 0° C. and chromatographed on silica (eluant: ethyl acetate-cyclohexane 7-3) to obtain 7.49 g of the desired compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[O:17][C:18]([CH2:23][CH3:24])=[C:19]([CH2:21][CH3:22])[N:20]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[O:17][C:18]([CH2:23][CH3:24])=[C:19]([CH2:21][CH3:22])[N:20]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)O
Reactant: CCc1nc(N)oc1CC
Product: CCc1nc(NC(=O)c2cc(Br)ccc2OC(C)=O)oc1CC
Yield: 22 %

Procedure:
Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4,5-diethyloxazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.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>[OH:12][CH2:11][CH2:10][CH2:9][S:8][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]#[N:14])=[CH:2][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: OCCCSc1cccc(Br)c1
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: O
Solvent: CC#N
Product: N#Cc1ccccc1-c1ccc(SCCCO)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 71.2 %

Procedure:
3-(3-Bromophenylsulfanyl)propane-1-ol (0.49 g) was suspended in acetonitrile (8.5 mL), 4-cyanophenylboronic acid (0.34 g), sodium carbonate (0.42 g), water (1.7 mL) and tetrakis(triphenylphosphine)palladium(0) (0.12 g) were added, and the resulting mixture was stirred at 80° C. for 7 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.38 g).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>C(O)(C)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: [OH-]
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 86.2 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and tert-butanol (243.2 g) were mixed, and the resultant mixture was heated to 80° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (4 g) was added over three hours. Liquid chromatographic analysis revealed the reaction mixture contained 12.6 g of p-cyanobenzamide (yield 86%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][CH2:20][CH2:21][CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>O1CCOCC1>[NH:26]1[CH:27]=[C:23]([CH2:22][CH2:21][CH2:20][NH:19][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])[N:24]=[CH:25]1
Reactant: NCCCc1c[nH]cn1
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: CC1CC(=O)NN=C1c1ccc(NCCCc2c[nH]cn2)c([N+](=O)[O-])c1

Procedure:
2.67 g (10 mmol) of 6-(4-chloro-3-nitro-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone are boiled under reflux with 2.5 g (20 mmol) of 4-(3-aminopropyl)-1H-imidazole in 50 ml of dioxane for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].N1C=CC=CC=1.[CH:21]1[C:34]2[C:25](=[CH:26][C:27]3[C:32]([C:33]=2[S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]3[C:34]([C:33]=2[S:35]([NH:6][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:4]([OH:13])[C:3]([O:2][CH3:1])=[O:14])(=[O:37])=[O:36])=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C(O)[C@@H](N)c1ccccc1
Reactant: O=S(=O)(Cl)c1c2ccccc2cc2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](O)[C@@H](NS(=O)(=O)c1c2ccccc2cc2ccccc12)c1ccccc1
Reaction time: 1.5 h

Procedure:
(3S)-3-Phenylisoserine methyl ester (I, 0.38 g, 1.95 mmol) is dissolved in methylene chloride (5 mL) and pyridine (1 mL) and the solution treated with a suspension of 9-anthracenesulfonylchloride (0.536 g, 1.95 mmol). The reaction is stirred at 23° for 90 min. The reaction is then poured into methylene chloride and extracted with hydrochloric acid (1 N) and aqueous bicarbonate (5%) and dried over magnesium sulfate. Concentration of the organic layer under reduced pressure produces crude product. This concentrate is chromatographed (silica gel 60; ethyl acetate/toluene, 20/80) to give the title compound, TLC (silica gel GF) Rf=0.38 in (ethyl acetate/toluene, 2/8); NMR(CDCl3, TMS) 3.11, 3.57, 4.18, 4.78, 6.22, 6.59, 6.67, 7.50, 7.55-7.75, 7.92, 8.09, 8.47 and 9.15 δ
Reaction SMILES: [F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]Br>ClCCl>[F:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[C:5]([Br:13])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1F
Reactant: BrBr
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(F)c(Cl)c1F

Procedure:
19.2 g of 2,4-difluoro-3-chloronitrobenzene and 3 g of anhydrous FeCl3 are heated to +140° C., 5.1 ml of bromine are added dropwise with stirring, and the mixture is stirred for a further 48 hours at that temperature. The reaction mixture is cooled and is then taken up in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated. The residue is purified on a silica gel column using hexane/dichloromethane (10:1) as eluant. The title compound of formula ##STR10## is obtained in the form of a brown oil; refractive index nD25 : 1.5720.