Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCC#CCC1=CC(O)CC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCCC#CCC1=CC(O)CC1=O
Yield: 81.4 %

Procedure:
A stirred mixture of 5.8 g of 7-(4-hydroxycyclopent-2-en-1-on-2-yl)-5-heptynoic acid, 3.95 g of potassium carbonate, 7.4 g of iodomethane and 52 ml of acetone was refluxed for 2.5 hours. Most of the acetone was evaporated and the residue was partitioned with water and ether. The ether layer was separated, washed with brine, dried and concentrated, giving 5.02 g of the desired compound as an oil; PMR δ 3.72 (3H, s, methyl ester).
Reaction SMILES: [CH:1]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH:24]3[CH2:25][CH2:26][CH2:27][CH:20]2[C:21](=[CH:29]O)[C:22](=O)[CH2:23]3)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH:24]3[CH2:25][CH2:26][CH2:27][CH:20]2[C:21]2[CH:29]=[N:8][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:22]=2[CH2:23]3)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: NNC1CCCCC1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnn(C3CCCCC3)c1C2

Procedure:
Prepared as described in Example 5 using cyclohexylhydrazine and 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:10])([CH2:7][O:8][CH3:9])[CH2:5][OH:6].IC.[CH3:13]CO>CCOCC>[CH3:9][O:8][CH2:7][C:4]([NH2:3])([CH2:5][O:6][CH3:13])[CH3:10]
Reactant: CCO
Reactant: COCC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COCC(C)(N)COC
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a 3-necked 3 L RB flask equipped with overhead stirrer, condenser and N2 inlet line was added NaH (Morton Thiokol, Inc.-Alfa Products, 60% in mineral oil, 44 g, 1.1 mol). After washing with hexane (3×200 mL), dry THF (1.1 L) was added to the flask. After cooling to 0°, 2-amino-3-methoxy-2-methyl-1-propanol (61C, 119.16 g, 1.0 mol) was added dropwise to the flask at such a rate that the reaction temperature remained below 30°. The resulting slurry was cooled to 0°. Iodomethane (Aldrich, 141.94 g, 1.0 mol, 62.25 mL) was added dropwise to the mixture at such a rate that the reaction temperature remained below 30°. After the mixture was stirred for 1 h, EtOH (25 mL) was added to quench the reaction. The volume of the reaction was reduced to 200 mL. This material was diluted to 2 L with Et2O, filtered and the solvent removed. Fractional distillation of this material gave 91.02 g (68.3% yield of 1,1-bis-(methoxymethyl)ethylamine, bp 146°-149°, (C,H,N).
Reaction SMILES: [OH:1][CH:2]([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14].ClCCl>C1(C)C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:4][CH2:3][CH:2]([OH:1])[CH3:5])=[O:21])=[CH:23][CH:24]=1)([O-:15])=[O:14]
Reactant: CC(O)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)COC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 51 %

Procedure:
2-Hydroxypropanol (4.57 g) was dissolved in toluene (80 ml) by stirring and triethylamine (6.68 g) was dropped thereinto at 0° C. After stirring at the same temperature for 30 minutes, a solution of p-nitrobenzoyl chloride (11.4 g) dissolved in toluene (12 ml) was slowly added thereto. The resultant mixture was heated to room temperature and stirred for 2 hours. Next, dichloromethane (50 ml) was added and the crystals thus precipitated were dissolved. The solution was washed with an dilute aqueous solution of sodium hydrogencarbonate (100 ml) and then with an aqueous solution of hydrochloric acid (0.5 mol/l). The organic layer thus obtained was concentrated and the residue was dissolved in toluene (45 ml) by heating. Then it was cooled by allowed to stand at room temperature for crystallization. The crystals thus precipitated were collected by filtration and dried under reduced pressure to give 6.90 g (51%) of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Oc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Oc1ccc(F)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
To a stirred solution of 25 g of 4fluorophenol in 40 cc of pyridine and 30 cc of toluene was added dropwise 40.9 g of 2-chlorobenzoylchloride at room temperature. And the resulting mixture was stirred at room temperature for 16 hours. Ice water was added to the reaction mixture and extracted with ethyl acetate. The ethylacetate layer was washed 4 times with 1N HCl, dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was recrystallized from hexane to obtain 49.1 g of compound A. Yield: 87.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccnc(-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccnc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
Methyl 2-(4-fluorophenyl)isonicotinate (278 mg, 1.20 mmol) was dissolved in methanol (2 mL) and the solution was added with 2 mol/L aqueous sodium hydroxide solution (2 mL, 4.0 mmol), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure and the obtained reaction mixture was dissolved in water. The solution was washed with ethyl acetate, then was added with 1 mol/L hydrochloric acid, and the obtained crystal was collected by filtration to obtain 2-(4-fluorophenyl)isonicotinic acid (134 mg, 51%).
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.O[N:19]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C(Cl)Cl.C(N(CC)CC)C>[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([NH2:19])=[O:17]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C1CCCCN1
Reaction time: 72 h
Yield: 89 %

Procedure:
N-benzyloxypiperidine-2-carboxylic acid (2.0 g), 1-hydroxybenzotriazole (1.6 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.3 g) were dissolved in methylene chloride (20 mL). Concentrated aqueous ammonia (3 mL) and triethylamine (2 mL) were added to the resultant solution at room temperature, followed by stirring for 3 days. The reaction mixture was partitioned between water and methylene chloride. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. 10% Palladium-carbon (1 g, 50% wet) was added to the residue in methanol (30 mL), and the resultant mixture was stirred in a hydrogen atmosphere for 20 hours. The catalyst was removed by filtration. The solvent was evaporated under reduced pressure, and the thus-obtained oily product was dried, to thereby give the title compound as a solid (970 mg, quantitative amount).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18]C3CCCCO3)=[CH:13][CH:12]=2)=[C:5]([CH3:25])[N:4]=1>CO>[NH2:2][C:3]1[N:8]=[C:7]([OH:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=2)=[C:5]([CH3:25])[N:4]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(COC2CCCCO2)cc1
Agent: Cl
Solvent: CO
Product: Cc1nc(N)nc(O)c1Cc1ccc(CO)cc1
Reaction time: 0.5 h

Procedure:
Conc. HCl (4 ml) was added to a mixture of the product from example 34 step (ii) (5.2 g) in MeOH (100 ml) at rt and stirred for 30 min. The solvent was evaporated under reduced pressure and the residue dissolved in water (150 ml). Aq sat. NaHCO3 soln was added until basic then the solid filtered, washed with water, ether and dried to afford the subtitle compound, 3.48 g.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[C:6]([NH:8][C:9]1[S:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][N:13]=1)=[O:7].[H][H].I[CH2:24][C:25]([NH2:27])=[O:26]>CN(C)C=O>[CH3:3][C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[C:6]([N:8]=[C:9]1[N:13]([CH2:24][C:25]([NH2:27])=[O:26])[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[S:10]1)=[O:7]
Reactant: [H][H]
Reactant: NC(=O)CI
Reactant: Cc1ccccc1C(=O)Nc1ncc([N+](=O)[O-])s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N=c1sc([N+](=O)[O-])cn1CC(N)=O
Temperature: 25 °C

Procedure:
Sodium hydride in mineral oil (2.1 g, 60% w/w) was added in portions to a stirred suspension of 2-methyl-N-(5-nitro-2-thiazolyl)benzamide (10.5 g) in N,N-dimethylformamide (100 ml). When the evolution of hydrogen ceased, 2-iodoacetamide (11.1 g) was added in portions. The mixture was stirred at room temperature for ca 1 hr., then poured into ice-water. Recrystallization of the separated solid from acetic acid afforded 2-[(2-methylbenzoyl)imino]-5-nitro-4-thiazoline-3-acetamide, m.pt 248°-250°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.O[C:26]1[C:35]([OH:36])=[CH:34][C:33]([C:37]([F:40])([F:39])[F:38])=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)[O:36][C:35]3[CH:34]=[C:33]([C:37]([F:38])([F:40])[F:39])[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[C:26]=3[O:8]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(O)c1O
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)c1cc(C(F)(F)F)cc2c1OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)O2

Procedure:
4,4′-Dimethoxybenzophenone (213 mg, 0.88 mmol, 1.5 eq.), oxalyl chloride (900 mg, 7.1 mmol, 8 eq.) and methyl 2,3-dihydroxy-5-trifluoromethyl-benzoate (130 mg, 0.59 mmol, 1 eq.) were reacted according to GP2.2. The crude product was purified using flash chromato-graphy (silica gel, hexane/Et2O 10:1) to yield the title compound as a yellowish, very viscous oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][OH:12])[NH:2]1.[CH3:13][C:14](OC(C)=O)=[O:15].C([O-])([O-])=O.[K+].[K+].CC(O)=O>CCOC(C)=O.CO>[OH:12][CH2:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:14](=[O:15])[CH3:13]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N1Cc2ccccc2C[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (Aldrich, 350 mg, 2.14 mmol) in EtOAc (4.3 mL) and MeOH (1.1 mL) was added Ac2O (243 μL, 2.57 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. K2CO3 was then added to neutralize the AcOH, and the reaction mixture was filtered through a pad of CELITE®, washing with EtOAc. The filtrate was concentrated in vacuo to give the title compound (316 mg, 72%) as a white solid. 1H NMR (CDCl3, 1.5:1 mixture of amide rotamers) δ 7.26-7.10 (m, 4H), 5.17 (d, J=18.0 Hz, 0.5H), 4.90 (dt, J=5.1, 9.4 Hz, 0.5H), 4.66-4.44 (m, 1H), 4.39-4.23 (m, 1H), 3.66-3.55 (m, 1H), 3.55-3.45 (m, 1H), 3.14 (dd, J=5.9, 16.3 Hz, 0.5H), 3.02 (dd, J=6.2, 15.8 Hz, 0.5H), 2.92-2.76 (m, 1H), 2.27 (s, 1H), 2.24 (s, 2H); MS(ESI+) m/z 206.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC)=[C:6]([Cl:10])[C:5]([F:11])=[CH:4][C:3]=1Br.[Mg].[C:14](Cl)(=[O:16])[CH3:15].S(=O)(=O)(O)O.[O:23]1CCC[CH2:24]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:14](=[O:16])[CH2:15][O:23][CH3:24])=[C:6]([Cl:10])[C:5]([F:11])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1c(Cl)c(F)cc(Br)c1Cl
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Product: COCC(=O)c1c(Cl)ccc(F)c1Cl
Temperature: -30 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
0.20 mol of 2,4-dichloro-5-fluoro-3-methoxybromobenzene, 0.22 mol of powder of magnesium, 0.24 mol of cuprous chloride in 240 ml of tetrahydrofuran were stirred at ambient temperature to initiate the reaction, and then quickly cooled to −30±10° C. The reaction was monitored by TLC to be finished. A solution of acetyl chloride (0.30 mol) in 50 ml of toluene was added dropwise to the resulting mixture. The reaction was carried out at −30±110° C. for 8 hours. The temperature of the reaction was then increased to room temperature and stirred for 3 hours. The reactant was poured into a mixture of 170 g of crushed ice containing 75 ml of 25% aqueous solution of sulfuric acid. The resulting mixture was stirred for 5 minutes. The organic phase was separated off. The aqueous layer was extracted by toluene. The combined organic phases were washed successively with aqueous solution of sodium chloride, aqueous solution of sodium bicarbonate and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to afford 38.7 g of 2,4-dichloro-5-fluoro-3-methoxyacetylbenzene (0.163 mol) in 81.6% yield, mp. 36.7-39.4° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C>[CH3:4][N:3]1[C@H:2]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:7][C:6]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=4)=[CH:5][C:19]=3[CH2:20][CH2:11]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2ccccc2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5ccccc5n4)cc3CC[C@@H]12
Yield: 54 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 126 mg (54%) of the title compound as an amorphous foam. mp 140°-145°. FDMS: m/e=356. α[D]589 =+74.01 (c=0.46, chloroform).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8]O.Cl.[NH2:11][CH2:12][CH2:13][SH:14].C(O)(C)C.CO.[BrH:21]>>[BrH:21].[BrH:21].[CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[N:4]=[C:3]1[CH2:8][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1cn(C)c(CO)n1
Reactant: NCCS
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cn(C)c(CSCCN)n1

Procedure:
The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) with cysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by the method described in Example 1(i)(a) give 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2 g.), m.p. 161°-163° (from isopropyl alcohol-methanol).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].S(Cl)([Cl:19])(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F
Yield: 36.3 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 10.1 g (75.0 mmol) of sulfuryl chloride and 0.8 (5.0 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 11 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.8 g (purity: 83.4%, yield: 30.3%) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [NH:1]=[C:2]([NH:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[N:12]=1)=O)[CH3:3].O>C(O)CO>[CH3:3][C:2]1[NH:4][N:5]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:12]=2)[N:1]=1
Reactant: CC(=N)NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Solvent: OCCO
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)n[nH]1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of N′-(1-iminoethyl)-4-(4-(trifluoromethoxy)phenyl)thiazole-2-carbohydrazide (10.0 g, 33.0 mmol) in ethylene glycol (20 mL) was stirred at 180° C. for 2 h. After cooling to RT, H2O (100 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1) to afford the title compound as a white solid (9.6 g, 100%). MS (ES+) C13H9F3N4OS requires: 326. found: 327 [M+H]+; 1H NMR (500 MHz, DMSO) 8.27 (s, 1H), 8.15 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15])=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[N:35]1([CH2:41][C:42]2[CH:43]=[C:44]([CH:50]=[CH:51][CH:52]=2)[O:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:23]([NH:49][CH2:48][CH2:47][CH2:46][O:45][C:44]2[CH:50]=[CH:51][CH:52]=[C:42]([CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH:43]=2)=[O:24])[CH3:16])=[CH:4][CH:3]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CN(CCCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.78 g (2.6 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,3-propanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.65 g (2.6 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=576 ([M+H]+,7), 214 (100); IR (KBr): 1649 cm-1 (C=O). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 65°-67° C.
Reaction SMILES: [CH3:1][C@@:2]1([C:13]([OH:15])=O)[CH2:6][CH2:5][C@H:4]([C:7](=[O:10])[NH:8][CH3:9])[C:3]1([CH3:12])[CH3:11].C(Cl)(=O)C>C(OCC)(=O)C>[CH3:1][C@:2]12[C:3]([CH3:12])([CH3:11])[CH:4]([CH2:5][CH2:6]1)[C:7](=[O:10])[N:8]([CH3:9])[C:13]2=[O:15]
Reactant: CNC(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)C2CC[C@@](C)(C1=O)C2(C)C

Procedure:
To a solution of step 1 intermediate (4.5 g, 21 mmol) in ethyl acetate, acetyl chloride (5.25 mL, 73 mmol) was added and refluxed for 24 hours. After the reaction, ethyl acetate was removed under reduced pressure, crude material purified by column, using ethyl acetate and hexane. (3.7 g) 1H NMR (400 MHz, CDCl3) δ ppm: 0.8 (s, 3H), 0.9 (s, 3H), 1.1 (s, 3H), 1.60-1.61 (m, 1H), 1.71-1.83 (m, 1H), 1.88-1.95 (m, 1H), 2.11-2.2 (m, 1H), 2.65 (d, 1H), 2.91 (s, 3H). m/z (M+H): 196.1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][P:5]([OH:18])([O:7][CH2:8][C@@H:9]1[O:13][CH2:12][C@@H:11]([S:14][C:15](=[O:17])[CH3:16])[CH2:10]1)=[O:6].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[OH-:4].[C:15]([S:14][C@@H:11]1[CH2:12][O:13][C@@H:9]([CH2:8][O:7][P:5]([OH:18])([O:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:6])[CH2:10]1)(=[O:17])[CH3:16]
Reactant: CC(=O)S[C@@H]1CO[C@@H](COP(=O)(O)OCCBr)C1
Reactant: c1ccncc1
Solvent: CO
Product: CC(=O)S[C@@H]1CO[C@@H](COP(=O)(O)OCC[n+]2ccccc2)C1
Product: [OH-]

Procedure:
The title compound is prepared by the procedure of Example 90 using 0.50 g of product from Example 93, 3 ml of pyridine, 4 g of Amberlyst-21, and 10 ml of methyl alcohol to give 0.233 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.[CH2:34](Br)[CH:35]=[CH2:36]>CN(C)C=O>[CH2:30]([N:1]([CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1)[CH2:36][CH:35]=[CH2:34])[CH:28]=[CH2:29]
Reactant: C=CCBr
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1noc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 75.9 %

Procedure:
5.17 g (15 mmol) of crude 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 45 ml of N,N-dimethylformamide, 6.5 ml (37.5 mmol) of N-ethyldiisopropylamine and 3.63 g (30 mmol) of allyl bromide were stirred at room temperature for 1 hour. The reaction solution was evaporated and the residue was chromatographed on 250 g of silica gel while eluting with ethyl acetate. The uniform fractions having the larger Rf value were evaporated. There were obtained 4.84 g (76%) of 3-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]-[1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 125°-130°.