Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:15][F:16])([C:13]#[CH:14])[CH2:11][F:12])=[CH:5][CH:4]=1.COC(C)(C)C.CC(C)([O-])C.[K+].[Br:31]Br>CCCCCC.C(O)(C)(C)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([CH2:11][F:12])([C:13]#[C:14][Br:31])[CH2:15][F:16])=[CH:5][CH:4]=1
Reactant: C#CC(CF)(CF)Oc1ccc(C(F)(F)F)cc1
Reactant: BrBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: FCC(C#CBr)(CF)Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
An amount (13.9 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl ether was dissolved in a solvent consisting of a mixture of tert-butyl methyl ether (100 ml) and tert-butyl alcohol (150 ml). To the solution under cooling with ice, potassium tert-butoxide (7.1 g) was added under a nitrogen atmosphere; after stirring for a while, bromine (3 ml) was added dropwise. After the end of the dropwise addition, the mixture was stirred for 30 minutes under stirring with ice. Hexane was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride. The mixture was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (18.1 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=[O:22])[C:14]3[N:15]([N:17]=[C:18](C=O)[CH:19]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.O.O.[Rh](Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13](=[O:22])[C:14]3[N:15]([N:17]=[CH:18][CH:19]=3)[CH:16]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cn3nc(C=O)cc3c(=O)[nH]2)cc1
Agent: Cl[Rh](Cl)Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cn3nccc3c(=O)[nH]2)cc1
Temperature: 160 °C
Reaction time: 42 h

Procedure:
140 mg (0.473 mmol) 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carbaldehyde are dissolved in 1 ml diethyleneglycoldimethylether. 12 mg (0.028 mmol) 3-diphenylphosphanylpropyl(diphenyl)phosphane and 3.7 mg (0.014 mmol) rhodium(III)-chloride trihydrate are added. The reaction mixture is stirred for 42 hours at 160° C. The mixture is cooled to room temperature and partitioned between dichloromethane and water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 6-(4-tert-butyl-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one (“A15”) as colourless crystals; HPLC/MS: 1.88 (C), [M+H] 268.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+].C1COCC1>CO>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized from methyl 4-(biphenyl-4-yl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (156 mg, 0.49 mmol) and lithium hydroxide monohydrate (83 mg, 1.97 mmol), according to General Procedure 7. A 1:2 mixture of THF and methanol (15 mL) was used. The resulting product was purified by flash chromatography (Isco CombiFlash) eluting with a gradient of 0-80% EtOAc/Heptane to give the title compound: 135 mg, 90.6%. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.22-2.33 (m, 1H), 2.73-2.82 (m, 1H), 2.82-2.91 (m, 1H), 2.91-3.00 (m, 1H), 4.23 (t, J=7.20 Hz, 1H), 6.56 (s, J=1H), 7.24-7.32 (m, 3H) 7.37-7.43 (m, 2H), 7.50-7.55 (m, 2H), 7.57-7.61 (m, 2H); LCMS-MS (ESI+) 304.2 (M+H); HPLC (UV=100%), (ELSD=100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:31].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[C:8]([C:10](=[O:12])[NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([F:30])[C:24]=2[F:23])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cn1S(C)(=O)=O
Reactant: Nc1cccc(F)c1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)Nc2cccc(F)c2F)cn1S(C)(=O)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 1-methanesulfonyl-1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (290 mg, 1.17 mmol) in dry CH2Cl2 (5 mL) and DMF (2 drops) was added oxalyl chloride (220 mg, 1.73 mmol) at room temperature. The mixture was stirred for 1 hour and evaporated. The residue was dried on the vacuum pump for 4 hours and then dissolved in dry CH2Cl2 (5 mL). To this solution was added 2,3-difluoro-phenylamine (300 mg, 2.32 mmol) and triethylamine (240 mg, 2.37 mmol). The reaction mixture was stirred for another 1 hour then poured into 2N HCl solution. The aqueous solution was extracted with EtOAc and the combined organic layers were dried over MgSO4. After removal of solvent by evaporation, the residue was purified by flash column eluting with 20% EtOAc/hexanes to afford the title compound as a yellow solid (410 mg, 98%). MS (ES+): m/e=359.1 (M+H); LC/Method A/3.31 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[C:35]([O:37]CC)=[O:36]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18](=[O:22])[N:19]([CH3:21])[CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)=[CH:28][C:27]=1[C:35]([OH:37])=[O:36]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Product: CC(c1ccc(-c2ccc(Cl)c(C(=O)O)c2)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 165, step 3) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid. The product of this reaction was hydrolyzed in analogy to Example 141 to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=498.1 [M−H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:17])[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:17])[C:6]1[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(C)CCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCN(C)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a solution (10 ml) of ethyl 4-[(2-methoxyethyl) (methyl)amino]benzoate (467 mg, 1.97 mmol) in methanol was added 1M aqueous sodium hydroxide solution (10 ml), and the mixture was stirred at 50° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure, and water and diethyl ether were added to the residue. The organic layer was separated. The aqueous layer was neutralized with 1M hydrochloric acid (10 ml) and extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to give the title compound (340 mg, 82%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc2nccc(Br)c2c1
Reaction time: 3 h

Procedure:
To a solution of (4-bromoquinolin-6-yl)(4-chlorophenyl)methanone (0.25 g, 0.72 mmol) in THF (5 mL) was slowly added (4-chlorophenyl)magnesium bromide (1.08 mL, 1 M in THF) at 0° C. under the argon. The resulting solution was kept at 0° C. for 3 hr. The reaction was quenched with saturated NH4Cl at 0° C. and the aqueous mixture was extracted with EtOAc 2 times. The combined organics were concentrated and purified by silica column chromatography (20-30% EtOAc/hexanes) to yield (4-bromoquinolin-6-yl)bis(4-chlorophenyl)methanol. (M+H)+: 458, 460.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1N1CCNCC1
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (10.05 g, 63.39 mmol) in isopropyl alcohol (350 mL) at room temperature was added piperazine (27.48 g, 319.0 mmol) in one portion. After 2 hours, the solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane. The organic phase was dried (sodium sulfate), filtered and concentrated to a bright yellow solid. This material was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.74 (s, 1H), 2.98 (m, 4H), 3.43 (m, 4H), 6.73 (dd, 1H, J=8.1, 4.8 Hz), 8.11 (dd, 1H, J=8.1, 1.7 Hz), 8.32 (dd, 1H, J=4.4, 1.7 Hz); MS (DCI/NH3) m/e 209 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[C:16]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:15][N:14]=2)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[C:32](=[O:35])([O-])[O-].[K+].[K+].CO[CH:40](Cl)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][CH3:21])[C:16]([C:22]([O:31][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:35][CH3:32])=[CH:43][CH:42]=3)([C:23]([F:26])([F:25])[F:24])[C:27]([F:30])([F:28])[F:29])=[CH:15][N:14]=2)[CH2:11][CH2:12]1)(=[O:3])[CH3:2]
Reactant: COC(Cl)c1ccccc1
Reactant: CCCc1cc(N2CCN(CCOC(C)=O)CC2)ncc1C(O)(C(F)(F)F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(N2CCN(CCOC(C)=O)CC2)ncc1C(OCc1ccc(OC)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
2-{4-[5-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl)-4-propylpyridin-2-yl]piperazin-1-yl}ethyl acetate (211 mg, 0.461 mol) was dissolved in N,N′-dimethylformamide (2.3 mL), and added potassium carbonate (191 mg, 1.38 mmol) at room temperature. Under ice-cold conditions, methoxybenzyl chloride (125 μL, 0.923 mmol) was added, and the mixture was stirred at room temperature overnight. Subsequently, potassium carbonate (96 mg, 0.690 mmol) was further added at room temperature, methoxybenzyl chloride (63 μL, 0.462 mmol) was added under ice-cold conditions, and the mixture was stirred at room temperature for 8 hours. The reaction solution was added water, extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The title compound (479 mg) was obtained as a red-brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH:21]=[CH2:22].[Cl-].[NH4+]>CCOCC.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:17]([OH:18])[CH2:22][CH:21]=[CH2:20])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CC[Mg]Br
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C=O)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=CCC(O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
N-((1R)-1-Formyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.0 g, 20.0 mmol) was dissolved in ether (150 mL). The solution was cooled to -78° C. and allylmagnesium bromide (22 mL of a 1.0 M solution in ether, 22 mmol) was added dropwise. After addition, the solution was warmed to room temp. It was given onto 10% ammonium chloride solution in water (200 mL). The phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed with satd. sodium hydrogencarbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (260 g) with ethyl acetate/heptane 1:1 to give 4.00 g of N-((1R)-1-benzyl-2-hydroxypent-4-enyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37]#[N:38])=[CH:35][CH:34]=[C:33]([NH:39][CH:40]2[CH2:45][CH2:44][CH2:43][N:42]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[F:28])[N:4]=3)[CH2:41]2)[N:32]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1N
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(N4CCCC(Nc5ccc(C#N)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.2 mmol) of 5-chloro-7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 53A), 69.1 mg (0.25 mmol) of 2-amino-6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 20A) and 0.213 ml (1.23 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 34 mg (28% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)OCC
Yield: 77.3 %

Procedure:
The title compound (794 mg, 77%) was prepared as a colourless gum from (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (586 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Reactant: OC1CCNCC1
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCC(O)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
74 mg (0.73 mmol) of 4-hydroxylpiperidine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 100 mg (87%) of 2-[2-ethoxy-5-(4-hydroxyl-piperidine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: S(=O)(=O)(O)O.N.[C:7]1([O:17][CH3:18])[C:8](=[CH:10][CH:11]=[C:12]([CH:16]=1)[CH2:13][CH:14]=[CH2:15])[OH:9].C[N+]1C2C(=CC=CC=2)N=C2C=1C=CC=C2.C[O:35]S([O-])(=O)=O>CCCCCCCC.O>[CH2:15]([OH:35])/[CH:14]=[CH:13]/[C:12]1[CH:11]=[CH:10][C:8]([OH:9])=[C:7]([O:17][CH3:18])[CH:16]=1
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: COS(=O)(=O)[O-]
Agent: C[n+]1c2ccccc2nc2ccccc21
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCCCC
Product: COc1cc(/C=C/CO)ccc1O
Reaction time: 1.62 h

Procedure:
A dilute sulfuric acid solution or aqueous ammonia was dropwise added to the foregoing reaction solution for enzyme-activity determination from which the buffer is omitted (i.e., a solution comprising 50 μl of a 200 mM solution of eugenol in n-octane, 200 μl of a 50 mM aqueous solution of phenazine methosulfate and 675 μl of deionized water) to adjust the pH thereof from 5 to 7 and the resulting mixture is stirred at a temperature ranging from 25 to 55° C. for 15 to 180 minutes. After the completion of the reaction, the coniferyl alcohol is extracted from the reaction solution with an organic solvent such as ethyl acetate, chloroform, methylene chloride or ethyl ether, followed by purification thereof by a means such as silica gel chromatography, reverse phase liquid chromatography or vacuum distillation, optional discoloration with active carbon and vacuum drying to give colorless coniferyl alcohol powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: C=CC(=O)O
Reactant: c1nnn[nH]1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)CCn1cnnn1

Procedure:
4.5 g of tetrazole are stirred for 8 hours at 90° with 4.5 ml of acrylic acid and 15 drops of pyridine. After cooling, 150 ml of water are added to the reaction mixture and the whole is acidified with HCl (concentrated) and concentrated under reduced pressure in a rotary evaporator. The crystalline residue is digested three times with methyl ethyl ketone and the combined organic phases are dried over sodium sulphate. After concentration by evaporation, the crystalline residue is stirred with isopropanol/ether and filtered off.
Reaction SMILES: [CH2:1]([C@@H:3]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]1([CH3:22])[CH:23]=[CH:24][C:18]([S:15]([O:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[CH2:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](CO)COCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@@H](COCc1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Yield: 63.8 %

Procedure:
1.34 g (0.0069 mol) of 2-(R)-ethyl-3-benzyloxypropan-1-ol (XVIId-1), 12 ml of dichloromethane, 1.31 g (0.0069 mol) of tosyl chloride and 0.084 g (0.0007 mol) of 4-dimethylaminopyridine are introduced into a round-bottomed flask kept under an inert atmosphere. The mixture is cooled to 0° C. and then 0.89 ml (0.011 mol) of pyridine is added dropwise. After leaving overnight in a refrigerator, the mixture is hydrolyzed using a 10% aqueous citric acid solution. The phases are separated and the aqueous phase is extracted with ethyl ether. The combined organic phases are washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/cyclohexane=750:25). 1.54 g (0.0044 mol) of the title compound (XVIIId-1) are obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH2:14]1[C:19](=O)[CH2:18][C:16](=[O:17])[CH2:15]1.[NH2:21][C:22]1[N:26]([CH3:27])[NH:25][C:24](=[O:28])[CH:23]=1>>[CH3:27][N:26]1[C:22]2[NH:21][C:19]3[CH2:14][CH2:15][C:16](=[O:17])[C:18]=3[CH:8]([C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=3)[C:23]=2[C:24](=[O:28])[NH:25]1
Reactant: O=C1CCC(=O)C1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(OC(F)(F)F)cc1
Yield: 27.4 %

Procedure:
4-Trifluoromethoxybenzaldehyde (0.28 g, 1.5 mmol), 1,3-cyclopentadione (0.15 g, 1.5 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.17 g, 1.5 mmol) were processed as described in Example 1 to provide 0.15 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.3 (t, 2H), 2.68 (m, 2H), 3.49 (s, 3H), 4.72 (s, 1H), 7.18 (d, 2H), 7.23 (d, 2H), 9.5 (bs, 1H) 10.37 (s, 1H); MS (ESI−) m/z 364 (M−H)−; Anal. calcd for C17H14N3F3O3·0.25 H2O: C, 55.21; H, 3.95; N, 11.36. Found: C, 55.34; H, 3.78; N, 10.97.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.CO>[Zn].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Temperature: 50 °C

Procedure:
To a solution of Example 7A (0.106 g, 0.344 mmol) in a solvent mixture of methanol (2 mL) and acetic acid (2 mL) was added Zn powder (0.067 g, 1.03 mmol). The reaction was heated to 50° C. for 5 h, and was then cooled to room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound, which was used without further purification. MS (ESI) m/z 278 [M+H]+.