Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:20]([CH3:22])[CH3:21])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[O:11])[CH2:6][CH2:5]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[C:27](OC)[C:26]=1[O:36][CH3:37].C(N(CC)CC)C.[N-]=[C:46]=[O:47]>ClCCl>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[C:10]([CH:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([NH:1][C:32]([NH:31][C:28]2[CH:27]=[C:26]([O:36][CH3:37])[C:25]([O:24][CH3:23])=[C:30]([O:47][CH3:46])[CH:29]=2)=[O:33])[CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6]1)=[O:11]
Reactant: CC(C)C(N)CN1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Reactant: [N-]=C=O
Reactant: COc1ccc(N=C=O)c(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)NC(CN2CCC(C(=O)c3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (30 mg) in dichloromethane (3 mL) was treated with trimethoxyphenyl-isocyanate (30 mg) and triethylamine (1 mL, 0.3 M in dichloromethane) was added and the reaction mixture was stirred at ambient temperature overnight. A polystyrene trisamine resin (approx. 0.5 g, 3.5 mmol/g) was added to capture excess isocyanate, and stirring was continued for an additional 2 h. The resin was filtered and the filtrate was concentrated. Purification by column chromatography gave 1-{1-[4-(3,4-dichloro-benzoyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3,4,5-trimethoxyphenyl)urea (27.5 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[C:33]([O:34][CH3:35])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: COc1cc2ccccc2cc1CBr
Product: COc1cc2ccccc2cc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 3 (c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 2-bromomethyl-3-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C.[OH-].[Na+].CCCCCC>C(O)C>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:25])=[O:3])=[CH:17][CH:16]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Product: CCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)O

Procedure:
Analogously to the process described in Example 2, 13 g of α-[p-(1-cycloheptenyl)-phenoxy]-heptanoic acid ethyl ester and 29 ml of 2 N sodium hydroxide solution in 130 ml of ethanol give α-[p-(1-cycloheptenyl)-phenoxy]-heptanoic acid of melting point 69°-71° C (from cold hexane).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:38]1[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:45])[F:46])=[CH:40][CH:39]=1)(=[O:43])=[O:42]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(OC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-(trifluoromethoxy)benzenesulfonyl chloride (18 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethoxy)benzenesulfonamide (percentage yield: 87%), was obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1.Cl.[N:15]1([C:20](N)=[NH:21])C=CC=N1>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:20]([NH2:21])=[NH:15])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CNC(=N)N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
The mixture of 4-Aminomethyl-benzoic acid methyl ester HCl (15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol; was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g, 85.6 mmol) was added to the reaction mixture and then stirred at rt for 4 h to give clear solution. The reaction mixture was evaporated to dryness under vacuum. Saturated NaHCO3 solution (35 mL) was added to give nice suspension. The suspension was filtered and the filter cake was washed with cold water. The mother liquid was evaporated to dryness and then filtered. The two solids were combined and re-suspended over distilled H2O (50 ml). The filter cake was then washed with minimum quantities of cold H2O and ether to give 12.32 g white crystallin a solid intermediate 1 (77% yield, M+1: 208 on MS).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=[O:8].[BrH:24].N([O-])=O.[Na+].[C:29]([NH2:33])(=[O:32])[CH:30]=[CH2:31]>CC(C)=O.CO.O>[Br:24][CH:30]([C:29](=[O:32])[NH2:33])[CH2:31][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)=[O:8]
Reactant: C=CC(N)=O
Reactant: COc1ccc(N)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(CC(Br)C(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.26 g of 5-amino-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide in 27 ml of acetone and 11 ml of methanol were added 5.6 ml of 47% solution of hydrobromic acid, 540 mg of sodium nitrite and 2 ml of water under cooling with ice, and the mixture was stirred for 10 minutes. To the reaction mixture were added 3.00 g of acrylamide, and, after heated to 30° C., 135 mg of cupric oxide were added little by little, and the mixture was stirred further for 2 hours at 30° C. Solvent was distilled off under reduced pressure, and 25% aqueous ammonia was added to the residue, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, the residue obtained was crystallized from hexane:ethyl acetate=1:1, and then the crystals were collected by filtration to obtain 1.55 g of 5-(2-bromo-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals.
Reaction SMILES: C(OP(C[N+]#[C-])(=O)[O:5][CH2:6][CH3:7])C.C([Li])CCC.[CH2:17]1[C:21]2(C[CH2:25][CH2:24][CH2:23][C:22]2=O)[CH2:20][CH2:19][CH2:18]1.Cl>C(OCC)C.CCCCCC.O>[CH2:20]1[C:21]2([CH2:22][CH2:23][CH2:24][CH2:25][CH:7]2[CH:6]=[O:5])[CH2:17][CH2:18][CH2:19]1
Reactant: [C-]#[N+]CP(=O)(OCC)OCC
Reactant: O=C1CCCCC12CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: O=CC1CCCCC12CCCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl(isocyanomethyl)phosphonate (410 μL) in diethyl ether (5 mL) was cooled to −78° C. in nitrogen atmosphere. After addition of 1.54M n-butyl lithium solution in hexane (1.7 mL) to the reaction mixture at −78° C., the temperature was raised to 0° C. and stirred for 15 minutes. To the resulting solution spiro[4.5]decane-6-one (300 mg) was added at 0° C., and the temperature was raised to room temperature under stirring. An hour thereafter, conc. hydrochloric acid (5 mL) was added to the reaction mixture at room temperature, followed by further 10 hours' stirring. The resulting solution was diluted with water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off to provide the title compound in crude, unpurified form, as a colorless oily substance.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1.O.[OH-].[Na+].[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:1][CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1c2c(cc3c1OCO3)C(OC(C)=O)CN(C)C2
Reaction time: 1 h
Yield: 99 %

Procedure:
4.74 g (20 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6) was dissolved in 70 ml of methylene chloride, to which 1.71 ml of acetyl chloride was added dropwise at room temperature. This solution was stirred at 20°-30° C. for one hour, added with 30 ml of water and then further added with 25% aqueous solution of sodium hydroxide to make the water layer basic. After separating the layers, the water layer was extracted with 20 ml of methylene chloride. The methylene chloride layers were joined together and washed with 30 ml of water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.53 g of 4-acetoxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (9) as a crystal (yield: 99%). This was then recrystallized from ethanol/n-hexane. Melting point: 109°-110° C.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=[O:25])=[CH:18][C:17]=1[O:27][CH3:28])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CC(C)=O>[C:2]([NH:1][C:5]1[CH:11]=[CH:10][C:8]([O:9][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]2[CH:20]=[CH:21][C:16]([O:15][C:12](=[O:14])[CH3:13])=[C:17]([O:27][CH3:28])[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:4]
Reactant: COc1cc(/C=C/C(=O)Cl)ccc1OC(C)=O
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(/C=C/C(=O)Oc2ccc(NC(C)=O)cc2)ccc1OC(C)=O
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of paracetamol (2.56 g, 16.92 mmoles) in pyridine (20 ml) cooled in an ice bath trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoyl chloride (4.31 g, 16.92 mmoles) dissolved in acetone (45 ml) is dropped. The mixture is maintained under stirring in ice for 3 hours then it is poured into water (300 ml) and the precipitate is filtered and triturated with hexane to give trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid 4-(acetylamino)phenyl ester (4.38 g) as an orange solid. M.p. 246-250° C. Yield 70%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1cc2[nH]ncc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc2cnc(Cl)cc21
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To a mixture of 6-chloro-1H-pyrazolo[4,3-c]pyridine (12.82 mmol; 1968 mg) in Dichloromethane (50 mL) was added N,N-Diisopropylethylamine (38.45 mmol, 6.7 mL). 2-(Trimethylsilyl)ethoxymethyl chloride (19.22 mmol; 3205 mg; 3.40 mL) was then added dropwise at room temperature. The resulting mixture was stirred overnight. The mixture was partitioned between DCM and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford 2-[(6-chloropyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (590 mg, 13%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:12]/[C:13]([OH:15])=[O:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(F)ccc1C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1cc(F)ccc1/C=C/C(=O)O
Temperature: 70 °C
Yield: 68.9 %

Procedure:
A stirred solution of 4-fluoro-2-methyl-benzaldehyde (20 g, 144.9 mmol) and malonic acid (30.1 g, 289.8 mmol) in pyridine (100 mL) was heated to 50° C. Piperidine (10 mL) was added and the reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled RT and poured into chilled aqueous 1N HCl solution (1500 mL), the resulting precipitate was filtered and washed with petroleum ether 60-80 and dried in vacuo to obtain (E)-3-(4-fluoro-2-methylphenyl)acrylic acid (18 g, 69%) as an off white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][C@H:26]([CH3:28])[N:25]([CH3:29])[C@H:24]([CH3:30])[CH2:23]2)=[CH:18][CH:17]=1.BrC1C=C2C(=CC=1)[C:38](=[O:42])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:42][CH3:38].[CH3:30][CH:24]1[N:25]([CH3:29])[CH:26]([CH3:28])[CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH2:15])=[CH:21][CH:20]=2)[CH2:23]1
Reactant: C[C@@H]1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)C[C@H](C)N1C
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CC1CN(c2ccc(N)cc2)CC(C)N1C
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 0.089 g (56.7% yield) of light brown solid is obtained from 0.10 g (0.30 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, and 0.073 g (0.33 mmol) of 4-(3,4,5-trimethyl-piperazin-1-yl)-phenylamine after purified by column chromatography over silica gel using 5% MeOH/CHCl3 as eluent: mp 224-225° C.; MS (ESI) m/z 517.1 (M+H)+1
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[C@H:9]2[CH2:17][C@@H:16]3[O:18][C@:15]3([CH3:19])[C@@H:10]2[CH:11]([OH:14])[O:12][CH:13]=1)=[O:7].[Cl:20][CH2:21][C:22]([N:24]=[C:25]=[O:26])=[O:23]>CCCCCC.C(OCC)(=O)C>[CH3:4][O:5][C:6]([C:8]1[C@H:9]2[CH2:17][C@@H:16]3[O:18][C@:15]3([CH3:19])[C@@H:10]2[C@@H:11]([O:14][C:25](=[O:26])[NH:24][C:22](=[O:23])[CH2:21][Cl:20])[O:12][CH:13]=1)=[O:7]
Reactant: O=C=NC(=O)CCl
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@@H]1C[C@@H]1O[C@@]12C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=CO[C@H](OC(=O)NC(=O)CCl)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
A dichloromethane solution containing 100 mg of a known (4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-hydroxy-7-methylcyclopenta[c]pyrane-4-carboxylic acid methylester was cooled with ice followed by addition of chloroacetylisocyanate (45 ml) and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1R,4aS,6S,7R,7aR)-1-(chloroacetylcarbamoyloxy)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c]pyrane-4-carboxylic acid methylester (137 mg, yield: 91%). The physicochemical properties of this compound are described in Table 8, Compound No. 40.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.[I-].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>O1CCCC1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][CH2:42][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Agent: [I-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)CCOc1c(C(=O)c2cc(C)c3c(c2C)C(C)(C)CCS3(=O)=O)c(C)nn1C
Temperature: 25 °C
Yield: 44.3 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of tetrahydrofuran, and further, 0.27 g (3.5 mmol) of pyridine and 90 mg of potassium iodide were added. Then, 0.63 g (3.5 mmol) of ethyl 2-bromopropionate was added, and the mixture was refluxed under heat for 7 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was extracted by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and the solvent was distilled off under reduced pressure to give 0.57 g (yield 45%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(1-ethoxycarbonyl)ethoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 40).
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl.C(OCC)(=O)C>N1C=CC=CC=1>[C:15]([O:10][C:9]1[CH:11]=[CH:12][C:4](/[CH:3]=[CH:2]/[C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:17])[CH3:16]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Reaction time: 24 h
Yield: 84.7 %

Procedure:
To a solution of ferulic acid (5 g, 25.75 mmoles) in pyridine (75 ml) cooled to 0° C. and sheltered from light, acetic anhydride (13.14 g, 128.7 mmoles) is added in small aliquots. When the addition is ended the temperature is let reach the room value maintaining the solution under magnetic stirring for 24 hours. HCl 18.5% (160 ml) is added up to pH 2, one extracts with ethyl acetate and the organic phase is anhydrified and the solvent is evaporated at a reduced pressure. 5.15 g of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid are obtained as a white solid. M.p. 199-205° C. Yield 85%.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][NH:19][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:26]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27]1.[Cl-:33].[NH4+]>ClCCCl>[ClH:33].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][N:19]([CH2:31][CH:28]2[CH2:29][CH2:30][O:26][CH2:27]2)[CH2:20][C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [Cl-]
Reactant: O=CC1CCOC1
Reactant: CN(C)C(=O)CNCCc1cccc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C(=O)CN(CCc1cccc(OCc2ccccc2)c1)CC1CCOC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1.06 g (22 mmol) of NaBH4 were added portionwise to a mixture 2.9 g (9.3 mmol) of 2-[2-(3-benzyloxy-phenyl)-ethylamino]-N,N-dimethyl-acetamide, 1.28 ml (14.1 mmol) of tetrahydrofuran-3-carbaldehyde and 4 g of 4 Å molecular sieves in 130 ml of 1,2-dichloroethane. The reaction mixture was stirred at room temperature overnight. Aqueous ammonium chloride was added, the solvent was removed under vacuum, the residue was extracted with ethyl acetate and the organic phase was washed with an aqueous saturated solution of K2CO3. The solvent was removed under reduced pressure and the product was dissolved in anhydrous hydrochloric acid in ethyl acetate. The solvent was removed and the product was triturated with diethyl ether. 3.2 g (80% yield) of the title compound were isolated as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C:52]1([F:58])CCNCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C:52]([F:58])([F:51])[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CCC(F)(F)CC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4,4-difluoropiperidine hydrochloride and isolated as light-yellow gum (10.9 mg, 55%). MS (m/e): 421.4 (MH+).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]2([CH3:13])[CH2:11][C:10](=[O:12])[NH:9][NH:8]2)=[CH:3][CH:2]=1.[Cl:20]Cl>C(O)(=O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:1]2[CH:6]=[CH:5][C:4]([C:7]3([CH3:13])[CH2:11][C:10](=[O:12])[NH:9][NH:8]3)=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: CC1(c2ccc(-c3ccccc3)cc2)CC(=O)NN1
Reactant: ClCl
Solvent: CC(=O)O
Product: CC1(c2ccc(-c3ccc(Cl)cc3)cc2)CC(=O)NN1

Procedure:
25.2 g of 3-(4-biphenylyl)-3-methyl-pyrazolidin-5-one are dissolved in 200 ml of acetic acid, a solution of 7.1 g of chlorine in 200 ml of acetic acid is added dropwise while stirring, and the mixture is stirred for a further hour and evaporated. Working up in the usual manner gives 3-(4'-chloro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 214°-215°.