Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=3[N+:25]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCC[CH2:31]1.C(OCC)(OCC)OCC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=4[N:25]=[CH:31]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: NC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of the 1.00 g (2.49 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b), 40 mL of saturated aqueous ammonium chloride solution and 40 mL of tetrahydrofuran was added 1 g of zinc powder. The mixture was stirred room temperature for 15 minutes, then another 1 g of zinc powder was added. The mixture was stirred at room temperature for 15 minutes, then 1 g of zinc powder was added, and the mixture was stirred at room temperature for 15 minutes until the organic layer became straw yellow in color. Subsequent manipulations were performed under nitrogen. The mixture was filtered, and the filtrate was partitioned between 30 mL of saturated ammonium chloride solution and tetrahydrofuran (1:1). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a reddish yellow solid. The solid was mixed with 40 mL of acetic acid and 0.82 ml, (4.98 mmole) of triethyl orthoformate, and the mixture was stirred at room temperature for 30 minutes, during which time the mixture became mostly homogeneous. The mixture was filtered and the filtrate was poured into 200 mL of water. The precipitate was collected by filtration, washed with water and air-dried to give 0.73 g of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.2a) as a pink solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:18][CH3:19])(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15]>>[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:3])=[O:15])([O:18][CH3:19])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)CCCCCCCCC(=O)O
Product: COC(=O)CCCCCCCCC(=O)Cl
Reaction time: 2 h

Procedure:
Thionyl chloride (360 g) was added dropwise to methyl hydrogen sebacate (432.6 g, 2 moles) at 60° C. with vigorous stirring and stirring was continued for 2 h under reflux. The reaction mixture was evaporated and the residue was distilled under reduced pressure to give the title compound as a colorless oil; yield: 400 g; bp 145°-150° C./4 mmHg. (Lit. bp 166°-168° C./14 mmHg; T. D. Heyes, J. C. Roberts, J. Chem. Soc., 1952, 4935).
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.CN(C)P(=O)(N(C)C)N(C)C.C[Si](C)(C)N[Si](C)(C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH2:28]([S:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nnc(S)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: Cc1nnc(SCc2ccccc2)s1
Reaction time: 0.17 h

Procedure:
2.0 mg (0.004 mmoles) of di-4-nitrophenyl N-(4-toluenesulfonyl)phosphoramidate were added to a solution of 264 mg (2 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole in 5 ml of toluene and 1.06 ml (6.1 mmoles) of hexamethylphosphoric triamide and then while refluxing, 0.50 ml (2.4 mmoles) of hexamethyldisilazane were added. After refluxing for 1.5 hours, the solution was evaporated to dryness and the residue was dissolved in 4 ml of acetonitrile. 0.28 (2.3 mmoles) of benzyl bromide were added to the solution and it was established that the conversion was complete after stirring for 10 minutes. HPLC analysis of the reaction mixture indicated a quantitative yield of 5-benzylthio-2-methyl-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:21][CH3:22])[C:17]=1[CH:18]([CH3:20])[CH3:19])[CH2:6]P(=O)(OCC)OCC.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>>[CH3:22][O:21][C:16]1[CH:15]=[C:5]([CH:6]=[CH:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:17]=1[CH:18]([CH3:19])[CH3:20]
Reactant: O=Cc1cccs1
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Product: COc1cc(C=Cc2cccs2)cc(OC)c1C(C)C
Yield: 78 %

Procedure:
This material was prepared from diethyl (3,5-dimethoxy-4-i-propylbenzyl)phosphonate obtained in example 15(a) and thiophene carboxaldehyde in 78% yield as the same way as described in the example 15(b), 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.70 (qint., J=7.1 Hz, 1H), 3.89 (s, 6H), 6.69 (s, 2H), 6.90 (d, J=16 Hz, 1H), 7.0-7.3 (m, 4H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[C:41]([CH3:46])=[N:42][O:43][C:44]=2[CH3:45])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[C:41]([CH3:46])=[N:42][O:43][C:44]=2[CH3:45])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cc2c(C)noc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2c(C)noc2C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.57 g), sodium hydrogen carbonate (0.78 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(3,5-dimethylisoxazol-4-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.26 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccc2ccsc2c1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2cc(-c3ccc(F)cc3)sc2c1
Yield: 54.1 %

Procedure:
To a 5 mL microwave vial was added a solution of 6-methoxybenzo[b]thiophene (400 mg, 2.44 mmol) in anhydrous DMA (3 mL) followed by 1-bromo-4-fluorobenzene (448 mg, 2.56 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 97 mg, 0.12 mmol), trimethylacetic acid (746 mg, 7.31 mmol) and potassium carbonate (1.01 g, 7.31 mmol). The microwave vial was sealed, purged with nitrogen and subjected to microwave irradiation at 150° C. for 2 h. Upon completion the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified via trituration 2× with heptane and the remaining triturate (containing some product) was concentrated and purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford 2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene (340 mg, 1.32 mmol, 54% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=3.79-3.93 (m, 3H), 7.01 (dd, J=8.59, 2.53 Hz, 1H), 7.24-7.42 (m, 2H), 7.56 (d, J=2.53 Hz, 1H), 7.67-7.86 (m, 4H). LC/MS (m/z, MH+): 258.8.
Reaction SMILES: C[C:2](P(OC)(O)=O)([C:4]([O-:6])=[O:5])[CH3:3].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:22]([C:25]1[O:29][C:28](C=O)=[CH:27][CH:26]=1)[CH2:23][CH3:24]>C1COCC1>[CH2:22]([C:25]1[O:29][C:28]([CH:3]=[CH:2][C:4]([O:6][CH3:12])=[O:5])=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: CCCc1ccc(C=O)o1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCc1ccc(C=CC(=O)OC)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a solution of trimethylphosphonoacetate (12.34 g; 61.6 mmol) in 500 mL of THF cooled to -78° C. under nitrogen with stirring, 136 mL (61.6 mmol) of 0.5M potassium bis(trimethylsilyl)amide was added dropwise over a 1/2 h period. The reaction mixture was stirred continuously at -78° C. for 1 hr. To the mixture was added 8.5 g (61.6 mmol) of 5-propyl-2-furancarboxaldehyde and 3 mL of THF over a 10 min period with stirring. After 1 h, stirring was stopped and the reaction mixture was allowed to warm to room temperature over a 2 h period. The reaction mixture was quenched with an aqueous solution of saturated ammonium chloride with stirring, and water was added to dissolve the precipitated salts into solution. The THF/aqueous solution was washed with ether (200 mL), and the aqueous layer was washed again with 100 mL of ether. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield 10.95 g (87.9%) of methyl 3-(5-propyl-2-furanyl)prop-2-enoate.
Reaction SMILES: [Cl:1]/[C:2](/[CH3:7])=[CH:3]\[C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4](=[O:5])/[CH:3]=[C:2](\[Cl:1])/[CH3:7])(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: C/C(Cl)=C/C(=O)Cl
Reactant: CCCC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc(NC(=O)/C=C(/C)Cl)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
29.2 g of β-chlorocrotonyl chloride were added over one hour at 0° C to a mixture of 31 g of m-amino-butyrophenone 21.2 g of triethylamine and 300 ml of tetrahydrofuran and after stirring for 16 hours at 20° C, the mixture was vacuum filtered. The filtrate was concentrated to dryness and the residue was chromatographed over silica gel to obtain 25 g of m-butyryl-3-chlorocrotonanilide melting at 106° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.Cl.Cl.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH:26]1[CH2:31][N:32]([CH3:34])[CH3:33])(=[O:24])=[O:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]([CH2:31][N:32]([CH3:34])[CH3:33])[CH2:27]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CN(C)CC1CNCCN1S(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
To a mixture of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (140 mg) and (1-methanesulfonyl-piperazin-2-ylmethyl)-dimethyl-amine dihydrochloride (140 mg) in dry MeCN (6 mL) was added K2CO3 (190 mg). The mixture was stirred at 80° C. for 4 h. An aqueous work-up followed by purification on silica gave [4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-methanesulfonyl-piperazin-2-ylmethyl]-dimethyl-amine (115 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:12])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCCC3)c2)n1
Yield: 47.8 %

Procedure:
3-(Cyclopentyloxy)-5-[(phenylmethyl)oxy]benzoic acid (3.14 g, 10.0 mmol), 1-methyl-1H-pyrazol-3-amine (1.95 g, 20 mmol) and HATU (4.95 g, 13 mmol) were dissolved in DMF (12.5 mL) then DIPEA (3.49 mL, 20 mmol) was added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL) and extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4), filtered and concentrated in vacuo to leave a yellow oil. The residue was chromatographed on silica, eluting with 0-30% ethyl acetate in isohexane, to give the desired product as a clear gum (1.87 g).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([OH:31])=O)[C@H:25]([CH2:27][CH3:28])[CH3:26].O.[NH:40]1[CH2:54][CH2:53][CH2:52][C@@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([N:40]1[CH2:54][CH2:53][CH2:52][C@@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])=[O:31])[C@H:25]([CH2:27][CH3:28])[CH3:26]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 72 %

Procedure:
While cooling on ice, DCC (8.3 g, 30 mmol) and triethylamine (3.5 ml, 25 mmol) were added to DMF (200 ml) containing Boc-L-Ile-OH.1/2 H2O (24.0 g, 100 mmol), H-D-Pro-OBzl-HCl (19.3 g, 80 mmol), and HOBt.H2O (15.3 g, 100 mmol). After stirring for 8 hours, DMF was removed by evaporation, the residue was dissolved in ethyl acetate, and then successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. After drying over MgSO4 and concentrating, the resulting oily substance was purified by flash silica gel chromatography (4×30 cm, 1% methanol/chloroform) to obtain the oily title compound (21.5 g, 51 mmol, 72% yield). TLC: Rf=(CHCl3/MeOH=9/1)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[C:5]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:18][CH:17]=2)[CH:4]=1.[CH2:34](N(CC)CC)[CH3:35].[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>C(Cl)Cl>[CH2:41]([NH:43][C:44](=[O:45])[NH:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([O:11][CH2:34][CH3:35])=[O:10])=[C:5]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:18][CH:17]=2)[CH:4]=1)[CH3:42]
Reactant: CCN(CC)CC
Reactant: CCN=C=O
Reactant: Nc1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Agent: Cl
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(OCC(=O)OCC)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 200 mg of ethyl (4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 40.5 mg of triethylamine and 5 mg of methylene chloride was added 30 mg of ethyl isocyanate followed by stirring at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68 to obtain 130 mg of ethyl 4-(3-ethylureido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:58][N:59]2[CH:63]=[N:62][CH:61]=[N:60]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:56])[CH:40]([NH:42][CH:43]6[CH2:48][CH2:47][N:46](CC7C=CC=CC=7)[CH2:45][CH2:44]6)[CH3:41])[C:35]5=[O:57])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:58][N:59]2[CH:63]=[N:62][CH:61]=[N:60]2)[O:13][CH:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH:38]=[N:37][N:36]([CH:39]([CH3:56])[CH:40]([NH:42][CH:43]6[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]6)[CH3:41])[C:35]5=[O:57])=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][O:10]1.[CH:12]([O:13][CH:9]([CH3:58])[CH3:3])([CH3:14])[CH3:11]
Reactant: CC(NC1CCN(Cc2ccccc2)CC1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)OC(C)C
Product: CC(NC1CCNCC1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of [2S-[2α,4α(R*,S*)]]+[2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (0.0046 mol) in methanol (100 ml) was hydrogenated at room temperature for 72 hours with Pd on activated carbon 10% (2 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/(CH3OH/NH3) 95/5 to 90/10). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 3 g (84%) of [2S-[2α,4α(R*,S*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-(4-piperidinylamino)-1-methylpropyl]-3H-1,2,4-triazol-3-one diisopropylether(1:1) (compound 63).
Reaction SMILES: [C:1](=[O:4])([O-])[OH:2].[CH3:5]N(C)C1C=CC(C=N[N+:13]2[CH:17]=[CH:16][N:15](N=CC3C=CC(N(C)C)=CC=3)[C:14]=2C=CN(C)C)=CC=1>CO.C(O)(=O)C>[C:1]([O-:2])(=[O:4])[CH3:5].[NH+:13]1[CH:17]=[CH:16][NH:15][CH:14]=1
Reactant: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: O=C([O-])O
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)[O-]
Product: c1c[nH+]c[nH]1
Reaction time: 0.33 h

Procedure:
1.0 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium hydrogen carbonate is dissolved in 20 ml of methanol and 3 ml of glacial acetic acid. After 20 minutes, the solution is concentrated at room temperature in a vacuum. The product is crystallized by the addition of ether and recrystallized three times from methanol/ether. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[2-dimethylamino)vinyl]imidazolium acetate of melting point 182° (dec.).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[C@H:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[OH:15].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Cl>CCCCCC.O1CCCC1>[OH:15][C@H:14]([C:13]([O:23][CH2:24][CH3:25])=[O:22])[C@H:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: CCOC(=O)C[C@H](O)C(=O)OCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](O)[C@@H](CC(=O)OC(C)(C)C)C(=O)OCC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
31 ml of 1.69M n-butyllithium in hexane was dissolved in 30 ml of tetrahydrofuran, stirred with 7.1 ml of diisopropylamine under cooling with ice for 30 minutes and then cooled to -78° C. 4.94 g of diethyl (S)-malate in 20 ml of tetrahydrofuran was added dropwise at -50° C. or below, and the reaction solution was stirred at -20° C. for 1.5 hours. The reaction solution was cooled to -78° C., and 5.58 g of tert-butyl bromoacetate and 4.66 g of hexamethylphosphoryl triamide in 20 ml of tetrahydrofuran were added dropwise at -50° C. or below. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into 150 ml of 0.5N hydrochloric acid and extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1→4/1] to give 3.88 g of the title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.Cl.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@@H:31]3[C@@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][N:36](CC4C=C5C(C=CC(=O)O5)=CC=4)[CH2:35][CH2:34]3)[N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[ClH:1].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[C@@H:31]3[C@@H:26]([CH2:27][CH:28]=[CH:29][CH2:30]3)[C:25](=[O:32])[N:24]([CH:33]3[CH2:38][CH2:37][N:36]([CH:3]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)[CH3:2])[CH2:35][CH2:34]3)[N:23]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(C2=NN(C3CCN(Cc4ccc5ccc(=O)oc5c4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(C)N4CCOCC4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 4-(2-chloroacetyl)morpholine and starting compound A1 as described for compound 18. M. p. 159-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:18][CH3:19])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:10]#[N:11].CS(C)=[O:22].O.[OH-].[Na+]>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)([CH2:18][CH3:19])[C:10]([NH2:11])=[O:22]
Reactant: CCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Temperature: 91 °C
Yield: 79 %

Procedure:
To a 1 liter flask was charged 206.5 g (0.7 mole) of alpha-(2,4-dichlorophenyl)-alpha-ethyl-1H-1,2,4-triazole-1-propanenitrile and 500 mL of dimethyl sulfoxide and 200 mL of water. To the stirring solution was added 67.2 g (0.84 moles) of 50% sodium hydroxide. The reaction mixture was heated at 91 ° C. (steam bath) for 3 hours after which GLC indicated the starting material was consumed. The reaction was cooled to 30° C. then poured into water and extracted with ethyl acetate. After drying, the ethyl acetate was treated with charcoal and filtered through Celite®. Removal of the solvent gave a foamy oil which was stirred and diluted with ethyl acetate then treated with hexane until cloudy. Within 1 hour a solid formed which was cooled at 0° C. The product was filtered and washed with an ether and hexane mixture, then dried and provided 172 g (79% yield) of a white solid, melting point 164°-165° C.