Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18]C(C)C(OC)=O)=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: COC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A mixture of 4-[N-methyl-N-(7-chloro-1,2,4-benzotriazin-3-yl)amino]phenol (1.5 g; Example 6 part (a)), ethyl 2-bromo-2-methylpropionate (1.23 g), anhydrous potassium carbonate (0.87 g) and dimethylformamide (15 ml) was heated, with stirring, at a temperature of 100° C. for a period of 3 days. The cooled solution was poured into dichloromethane and the mixture was washed with water. The aqueous phase was dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give an oil. The crude product was purified by chromatography over silica gel (eluent dichloromethane) to give the title compound (0.9 g) as a red oil.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+](C1C=CC([CH2:36][C:37]([O-])=[O:38])=CC=1)([O-])=O>CN(C)C=O>[C:37]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:38])[CH3:36]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.73 g (2.0 mmol) of methyl L-tyrosyl-L-valyl-L-alaninate (Example 1, Step A3) is dissolved in 5 ml of dimethylformamide, then 0.4 g (2.2 mmol) of p-nitro-phenyl-acetate is added. The reaction mixture is stirred at room temperature overnight then is evaporated at a pressure of 2.0-2.5 kPa. The residue is dissolved in 15 ml of ethyl acetate, the solution is washed with 3×5 ml of water, 5 ml of 1 M KHSO4 and 3×5 ml of water, then dried over anhydrous sodium sulfate and evaporated at a pressure of 2.0-2.5 kPa. The residue is rubbed with diethyl ether, filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:15]=[C:16]([Pb+3])[CH:17]=[CH:18][C:19]=1[Cl:20].[OH:22][C:23]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][N:31]=2)[NH:26][C:25](=[O:33])[CH:24]=1>CN(C)C1C=CN=CC=1.CS(C)=O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[C:25](=[O:33])[NH:26][C:27]3=[N:28][CH:29]=[CH:30][N:31]=[C:32]3[C:23]=2[OH:22])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=c1cc(O)c2nccnc2[nH]1
Reactant: Clc1ccc([Pb+3])cc1Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A mixture of 3,4-dichlorophenyl lead triacetate (1.63 g), 8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.254 g) and 4-dimethylaminopyridine (DMAP) (0.549 g) in anhydrous dimethylsulfoxide (10 mL) under a nitrogen atmosphere was heated to 60° C. for four hours. The reaction mixture was then allowed to cool to ambient temperature and stored at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate. The mixture was washed with aqueous hydrochloric acid (1M) and water, and the organic layer concentrated to give 7-(3,4-dichlorophenyl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (0.13 g) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:20])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[N:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)[CH:3]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(C(=O)C(=O)c2cccc(Br)c2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)C(=O)c2cccc(-c3ccncc3)c2)cc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of 1-(3-bromo-phenyl)-2-(4-methoxy-3-methylphenyl)ethane-1,2-dione (0.25 g, 0.75 mmol) in dioxane is treated sequentially with tri-o-tolylphosphine (57 mg, 0.187 mmol), palladium (II) acetate (21 mg, 0.093 mmol), pyridine-4-boronic acid (139 mg, 1.125 mmol) and H2O, stirred at 100° C. for 4 h, cooled to room temperature and filtered. The filtrate is evaporated in vacuo. The resultant residue is purified by flash chromatography on silica gel (hexanes/EtOAc 3/7 as eluent), to afford the title compound as a yellow solid, 0.145 g (58% yield), identified by HNMR and mass spectral analyses. MS m/e (M+H)+ 332; 1H NMR (400 MHZ, CDCl3) δ 2.28 (s, 3H) 3.95 (s, 3H) 6.94 (d, 1H) 7.68 (m, 3H) 7.84 (m, 2H) 7.88 (m, 1H) 8.08 (m, 1H) 8.30 (m, 1H) 8.75 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11](=O)[CH2:12]Br)=[CH:9][CH:8]=1)#[N:6].[OH-].[Na+].O>C(O)C>[NH2:1][C:2]1[S:3][CH:12]=[C:11]([C:10]2[CH:15]=[CH:16][C:7]([C:5]#[N:6])=[CH:8][CH:9]=2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
Thiourea (0.76 g, 10 mmol) was added to 4-cyanophenacyl bromide (2.0 g, 8.9 mmol) in ethanol (20 mL), and the reaction heated under reflux. After 45 min, the mixture was cooled to room temperature, and poured into 2N NaOH (10 mL)/water (40 mL). The precipitate was collected and air-dried to give 4-(2-amino-thiazol-4-yl)benzonitrile (1.6 g, 90%), which was used without further characterization.
Reaction SMILES: C(=O)([O-])O.[Na+].[Br:6]Br.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:6][C:16]1[CH:17]=[C:10]([O:9][CH3:8])[C:11]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:26]([CH3:28])[CH3:27])=[CH:12][C:13]=1[CH:14]=[O:15]
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)c(C=O)cc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
After adding 10.9 g of sodium hydrogen carbonate and 2.32 ml of bromine to a solution of 10g of 4-methoxy-3-triisopropylsilanyloxybenzaldehyde [CAS No. 179260-96-6] in 200 ml of chloroform at 0° C., the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium sulfite was then added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (11.7 g) as a light yellow oil.
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1cc(F)c(Br)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium (0.452 g) in tetrahydrofuran (20 mL), 1-bromo-2,4,5-trifluorobenzene (2.2 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for 30 minutes. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (4.0 g) in tetrahydrofuran (25 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 4.5 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: C[O-].[Na+].CO.[F:6][C:7]([F:14])([F:13])[C:8]([O:10]CC)=O.[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[N:16]1>C(OC(C)(C)C)C>[F:14][C:7]([F:6])([F:13])[C:8](=[O:10])[CH2:27][C:26]([C:23]1[CH:22]=[CH:21][C:20]([N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)=[CH:25][CH:24]=1)=[O:28]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2cccn2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-n2cccn2)cc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 63.4 %

Procedure:
A 5.4 N solution of sodium methoxide in methanol (3.0 mL, 16.2 mmol) was added drop wise over 10 min to a solution of ethyl trifluoro-acetate (1.81 mL, 15.2 mmol) in 2-ethoxy-2-methyl-propane (20 mL) at 20° C. followed by the addition of a suspension of 1-(4-pyrazol-1-yl-phenyl)-ethanone (2.57 g, 13.8 mmol) in 2-ethoxy-2-methyl-propane (10 mL). The reaction mixture was stirred for 22 h at 20° C. and then poured onto ice-water (50 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The remaining solid was recrystallized from ethyl acetate/heptane to give the title compound (2.47 g, 63%) as off-white solid. Mp 96° C.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[NH:28][N:27]=[N:26][N:25]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[CH3:37]CN(C(C)C)C(C)C>CC#N>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([C:24]4[N:28]([CH3:37])[N:27]=[N:26][N:25]=4)[CH:20]=[C:21]([F:23])[CH:22]=3)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(F)C(c1cc(F)cc(-c2nnn[nH]2)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Solvent: CI
Product: Cn1nnnc1-c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1

Procedure:
The reaction of mixture of 1.31 g (2.85 mmol) 5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole, 0.36 mL (5.70 mmol) methyl iodide, and 1.77 mL (9.97 mmol) DIEA in 8 mL MeCN was heated to reflux for 2.5 h. Then it was concentrated to remove the solvents. Then it was added 20 mL of CH2Cl2 and 5 mL of water and adjust pH=7-8 with aq NaHCO3. The water layer was extracted with CH2Cl2, and the combined organic layer was concentrated. The residue was separated by silica gel chromatography with CH2Cl2/MeOH/NH3 (2M) in MeOH to afford the title compound; 1H-NMR(CDCl3) δ 1.22(d, 3H, J=22 Hz), 1.29(d, 3H, J=22 Hz), 2.37 (t, 1H, J=8 Hz), 2.90 (t, 1H, J=8 Hz), 3.00 (m, 1H), 3.14 (m, 1H), 3.22 (m, 1H), 3.68 (J, 1H, J=6 Hz), 4.19 (s, 3H), 4.26 (s, 1H), 7.12-7.43 (m, 13H); Mass Spectrum: m/e=474 (M+1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[N:10]1[N:11]([CH2:15][C:16]2[CH:25]=[CH:24][C:19]([O:20][CH2:21][CH2:22]Br)=[CH:18][CH:17]=2)[N:12]=[CH:13][CH:14]=1>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][CH2:22][CH2:21][O:20][C:19]1[CH:24]=[CH:25][C:16]([CH2:15][N:11]2[N:12]=[CH:13][CH:14]=[N:10]2)=[CH:17][CH:18]=1
Reactant: BrCCOc1ccc(Cn2nccn2)cc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(OCCOc2ccc(Cn3nccn3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 5 ml of anhydrous N,N-dimethylformamide and 51 mg of sodium hydride (60% oil dispersion) is added dropwise an anhydrous N,N-dimethylformamide (3 ml) solution of 121 mg of 2-hydroxypyridine under stirring over 10 minutes. After stirring at room temperature for 1 hour, the mixture is cooled to 5° to 10° C., to which an anhydrous N,N-dirmethylformamide (2 ml) solution of 300 mg of 2-[4-(2-2H-1,2,3-triazolyl)methylphenoxy]ethyl bromide is added dropwise over 30 minutes. The mixture is then stirred at room temperature overnight. The reaction mixture is poured into 50 ml of ice water, which is extracted with twice with 30 ml of toluene. The organic layers are combined, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography, which affords 4-(2-2H-1,2,3-triazolyl)methylphenyl 2-(2-pyridyloxy)ethyl ether.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[F:7][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[F:7][C:8]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:9]=1[CH:10]([OH:11])[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: CC(C)C[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
To mixed solution of 2M isobutylmagnesium bromide in THF (6.25 mL) and ether (50 mL), was added dropwise a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (2.0 g, 10 mmol) in ether (18 mL) under N2 atmosphere. The mixture was stirred at room temperature for 45 minutes, to which was added saturated aqueous ammonium chloride solution and 1M hydrochloric acid under ice-cooling. The aqueous layer was extracted with ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated brine successively. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1), to give the titled compound as a yellow oil (601 mg, yield 23%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]2[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (300 mg, 099 mmol) in ethyl acetate (10 ml) were added 3-phenylpropionyl chloride (220 ml, 1.48 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (321 mg, 75%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:31])[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1.C1COCC1>C(OCC)(=O)C>[Cl:3][CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:31])[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CO)c3[nH]2)c(C)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CCl)c3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Thionyl chloride (3.22 mmol, 2.5 eq.) was added to a cooled (0° C.) solution of N-((7-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)methyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (1.29 mmol, 1.0 eq.) in abs. THF (10 ml). The reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with ethyl acetate and washed successively with NaHCO3 solution and NaCl solution. The organic phase was dried over Na2SO4 and the solvent was distilled off in vacuo to obtain the crude product, which led to the desired product by purification by column chromatography over silica gel. Yield: 76%
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Product: CC(C)=CCCC(C)=CC=O

Procedure:
100 parts of 3-methyl-2-buten-1-ol and 50 parts of 3,3-dimethylacrolein are heated for ninety minutes at 200° C and a pressure of 40 atmospheres in a rocking autoclave having a capacity of 250 parts by volume. The reaction product is worked up by distillation. 12.5 parts of citral is obtained having a boiling pont of 104° C at 12 mm. The yield (based on 3,3-dimethylacrolein) is 53% of theory at a conversion of 26%.
Reaction SMILES: [C:1](O)([C:3]([F:6])([F:5])[F:4])=O.[NH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]=2)=[CH:12][CH:11]=1)[NH2:9]>>[NH:19]1[CH2:18][CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]3[N:15]([C:1]([C:3]([F:6])([F:5])[F:4])=[N:9][N:8]=3)[N:14]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(NN)nn2)CC1
Product: FC(F)(F)c1nnc2ccc(C3=CCNCC3)nn12
Temperature: 70 °C
Reaction time: 24 h
Yield: 20.29 %

Procedure:
TFA (2 mL) was added in one portion to tert-butyl 4-(6-hydrazinylpyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (480 mg, 1.65 mmol) which dissolved with a vigorous effervescence. The solution was stirred for 24 hours at 70° C. The solution was evaporated and the residue was dissolved in methanol. It was run on an SCX cartridge, eluting with 2M ammonia in methanol. Product containing fractions were evaporated to dryness and triturated with ether to afford 6-(1,2,3,6-tetrahydropyridin-4-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (90 mg, 20.29%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[C:19]2\[C:20](=[O:31])[N:21]([CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:22][CH2:23]\2)/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[C:19]2\[C:20](=[O:31])[N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:23]\2)/[C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN1CC/C(=C(/c2ccc(Cl)cc2)c2ccc(S(C)(=O)=O)cc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C2\CCN(CCC(=O)O)C2=O)c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Yield: 81.9 %

Procedure:
1 g (0.0045 mole) of ethyl (Z)-3-[3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-oxo-pyrrolidin-1-yl]propanoate are placed in a solution in a mixture of 15 ml of ethanol and 20 ml of water and treated with 0.28 g (1.5 eq.) of sodium hydroxide. The medium is heated at 50° C. for 4 h. The ethanol was evaporated off and the aqueous phase is then extracted with ethyl acetate, acidified with a dilute hydrochloric acid solution, and extracted with dichloromethane. The organic phase is washed with water dried and concentrated. The residue is taken up into t-butyl methyl ether. 1.6 g of (Z)-3-[3-[1-(4-chlorophenyl)-1-[4-(methylsulphonyl)phenyl]methylene]-2-oxo-pyrrolidin-1-yl]propanoic acid are thus obtained as a beige solid of melting point 178-179° C.
Reaction SMILES: [Na].[CH2:2](O)C.[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[N:7]=1.C(#N)C(C)=C>ClCCl.CCCCCC>[NH2:5][C:6]1[CH:10]([CH3:2])[CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)[N:7]=1
Reactant: NC1=NN(c2ccc(Cl)cn2)CC1
Reactant: CCO
Agent: C=C(C)C#N
Agent: [Na]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1CN(c2ccc(Cl)cn2)N=C1N

Procedure:
As for Example 4 a 0.2 g. amount of sodium metal is dissolved in 50 ml. of absolute ethanol, then 5.0 g. of 5-chloro-2-hydrazinopyridine (Example 3) is added, followed by 4.8 g. of methacrylonitrile. The reaction mixture is refluxed for 18 hours. The solvent is removed in vacuo and water is added to give a gum which solidifies. The solid is collected by filtration, and washed with water. The solid is dissolved in dichloromethane, dried over magnesium sulfate and filtered through anhydrous magnesium silicate. The filtrate is evaporated and the residue is triturated with hexane to give a brown solid. The solid is dissolved in dichloromethane and hexane is added while concentrating to separate a solid. The mixture is cooled and filtered to give 3.4 g. of a gray solid. The desired product is recrystallized from dichloromethane-hexane to give a white solid, m.p. 159°-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(N(CC)CC)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 81.1 %

Procedure:
The same operation as in Example (227a) was performed using 4-[(tert-butoxycarbonyl)amino]piperidine (2.00 g, 9.99 mmol), benzyl chloroformate (2.14 mL, 15.0 mmol) and triethylamine (3.48 mL, 25.0 mmol), to obtain 2.71 g of the title compound as a white solid (81%).