Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Si:20]([O:27][CH2:28][CH:29]([OH:40])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:40][CH:29]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH2:28][O:27][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (0.5 g, 2.27 mmol) in DMP (10 ml) were added anhydrous cesium carbonate (0.74 g, 2.27 mmol) and 1-tert-butyldimethylsilyloxy 2-hydroxy 2-(4-tertbutylphenyl)ethane (0.7 g, 2.27 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]([CH2:16][C:17]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])#[N:15]>>[C:14]([C:16](=[CH:5][C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:17]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:18])#[N:15]
Reactant: CC(C)(C)COC(=O)CC#N
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(C)(C)COC(=O)C(C#N)=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 67 %

Procedure:
The procedure described in Example 4 was repeated using 3,4-dihydroxy-5-nitrobenzaldehyde and neopentyl cyanoacetate. Yield 67%, m.p. 173°-179° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1[CH-:13][C:12]([CH3:14])=[C:11]([CH3:15])[C:10]=1[CH3:16].[Na+]>C1COCC1>[CH3:8][C:9]1[CH:13]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]([CH3:14])=[C:11]([CH3:15])[C:10]=1[CH3:16]
Reactant: Cc1[cH-]c(C)c(C)c1C
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(C)=C(C)C(C)=C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.822 g (22.89 mmol) ethyl bromoacetate in 25 mL THF was cooled to -78° C. and 3.000 g (20.80 g) sodium tetramethylcyclopentadienide in 50 mL THF was slowly added to it. The resulting slurry was allowed to warm to room temperature and was stirred overnight. The solvent was removed, the residue was extracted with pentane and filtered. The pentane was removed to give a mixture of isomers. Yield was 3.733 g (86.3%). Mass spectra m/e 208 (41 percent).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (380 mg, 1.09 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (439 mg, 1.09 mmol) according to the general procedure M. Obtained as a red foam (150 mg, 20%).
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[N:29]1([C:35]2[N:44]=[C:43]([NH2:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:35]3[N:44]=[C:43]([NH2:45])[C:42]4[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=4)[N:36]=3)[CH2:30][CH2:31]2)=[O:12])=[CH:13][CH:14]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(C=CC(=O)O)cc1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccc(C(C)C)cc4)CC3)nc(N)c2cc1OC
Reaction time: 8 h

Procedure:
To a mixture of 342 mg. of 4-isopropylcinnamic acid and 727 mg. of triethylamine in 20 ml. of acetone were added dropwise under ice-cooling 195 mg. of ethyl chlorocarbonate and the resulting mixture was stirred for 3.5 hours. Then, 543 mg. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride were added thereto and stirring was continued at room temperature overnight. Then, the acetone was distilled off, the residue was dissolved in 20 ml. of 10% K2CO3 and extracted with ethyl acetate. After drying over magnesium sulfate, the extract was concentrated and recrystallization from methanol gave 361 mg. of the desired product.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20]>O>[CH2:11]1[NH:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([OH:18])[C@H:12]1[CH2:19][OH:20].[C:6]([C@@H:4]([C@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: OC[C@H]1CNC[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 0.17 h
Yield: 137.5 %

Procedure:
A solution of L-(+)-tartaric acid (102 mg, 0.679 mmol) in deionized water (1.0 mL) was added into the solution of isofagomine (200 mg, 2.0 equivalents) dissolved in deionized water (2.0 mL) at room temperature. The solution was stirred for 10 min and lyophilized overnight. The residue was further dried under vacuum at 45° C. for three days to afford the desired salt (275.6 mg, 91%). m.p. 92-93° C., 1H NMR (300 MHz, D2O): δ 4.22 (s, 2H), 3.71 (dd, J=12, 3.6 Hz, 1H), 3.67-3.59 (m, 2H), 3.44-3.37 (m, 3H), 2.85 (t, J=12 Hz, 1H), 2.75 (t, J=12 Hz, 1 H), 1.85 (m, 1H) (FIG. 8A)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][NH:4][C:3]1=[O:14].C(OC(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=O)C.C(=O)(O)[O-].[Na+].C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[O:14]=[C:3]1[C@@H:2]([N:1]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][NH:4]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@H]1CSC(c2cccs2)CNC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: O=C1NCC(c2cccs2)SC[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 7 h

Procedure:
19.1 g of 6(R)-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepine [prepared as described in step (d) above], 18 g of N-ethoxycarbonylphthalimide and 29 g of sodium bicarbonate were suspended in 150 ml of dimethylformamide. The suspension was stirred for 7 hours at 60° C. and then left standing overnight at room temperature. At the end of this time, 500 ml of water, 100 ml of diisopropyl ether and 20 ml of ethyl acetate were added, and the mixture was stirred to precipitate the title compound. This was collected by filtration, and washed with water and with a 5:1 by volume mixture of diisopropyl ether and ethyl acetate, giving 27.4 of the title compound, melting at 246°-247.5° C. (with coloration).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[Cl-].[Cl-].C([Al+2])C>C(Cl)Cl>[CH3:15][C:16]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]=1[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: Cc1ccc(C(=O)Cl)c2ccccc12
Reactant: Cc1cc2cccnc2n1CCN1CCOCC1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(C)n(CCN3CCOCC3)c3ncccc23)c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 4-methyl-1-naphthoyl chloride (112 mg, 0.55 mmol) and 4-(2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)ethyl)morpholine (143 mg, 0.59 mmol) in 2.5 mL CH2Cl2 at −70° C. was added dropwise ethyl aluminum dichloride (0.67 mL, 1.21 mmol, 1.8 M in toluene). The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then partitioned between ethyl acetate and cold H2O, and the aqueous layer extracted twice with ethyl acetate. The combined organic extract was washed successively with H2O, 10% K2CO3, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography using a gradient from 0 to 5% MeOH in CH2Cl2, then taken up in CHCl3 and washed with a saturated solution of Na2CO3, dried over Na2SO4, filtered, and concentrated in vacuo to give CBX003(32 mg, 0.077 mmol). 1H NMR (500 MHz, CDCl3, δ): 2.46-2.58 (m, 4H), 2.60 (s, 3H), 2.78 (t, J=6.8 Hz, 2H), 2.81 (s, 3H), 3.69 (t, J=4.5 Hz, 4H), 4.47 (t, J=6.8 Hz, 2H), 6.91-7.02 (m, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.43 (dd, J=7.9 Hz, 1.4 Hz, 1H), 7.45-7.52 (m, 2H), 7.58 (td, J=7.6 Hz, 1.1 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 8.26 (dd, J=4.7 Hz, 1.5 Hz, 1H). 13C NMR (500 MHz, CDCl3, δ): 12.83, 19.93, 39.55, 53.99, 57.68, 66.93, 113.29, 118.10, 119.85, 124.42, 125.76, 125.78, 126.06, 126.24, 126.66, 129.10, 130.36, 132.90, 137.15, 138.40, 143.02, 146.42, 147.59, 193.21. MS m/z 415.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:10][C:11]=1[NH2:12])=[O:5])[CH3:2].N1C=CC=CC=1.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:9][CH2:10][C:11]=1[NH:12][C:26]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Ethyl-4-amino-1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylate (23.6 g) was dissolved in methylene chloride (460 ml), and pyridine (13 ml) and phenyl chlorocarbonate (15 ml) were added under ice cooling and the resultant mixture was stirred for one hour at the same temperature. To the reaction solution, water was added and the mixture was extracted with methylene chloride. After the organic layer was washed sequentially with 1 N hydrochloric acid and saturated saline solution in this order, the organic layer was dried over sodium sulfate, filtrated and concentrated under reduced pressure. To the resultant residue, diethyl ether was added to obtain a precipitate by filtration. The titled compound (10.57 g) was obtained as a colorless solid substance. Furthermore, the filtrate was concentrated under reduced pressure. Thereafter, the resultant residue was purified by medium-pressure silica gel column (solvent; ethyl acetate:hexane=10:90 to 50:50). The resultant crude crystal was washed with a solvent mixture of diethyl ether-hexane to obtain the titled compound (11.10 g) as a slightly yellow solid substance.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1C
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1C[C@@H](C)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4S*)-4-amino-2-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f69) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1.CS(C)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:36]4[CH2:37][CH2:38][CH:33]([N:30]5[CH2:31][CH2:32][O:27][CH2:28][CH2:29]5)[CH2:34][CH2:35]4)=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cnn1-c1ccc(Cl)cc1
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c([N+](=O)[O-])c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
1-(4-Chlorophenyl)-N-(4-chloro-3-nitrophenyl)-5-methylpyrazole-4-carboxamide (1.6 g) and 4-morpholinopiperidine (2.4 g) were added to dimethyl sulfoxide (20 ml) and the mixture was stirred at a refluxing temperature for 1.5 h. After cooling to room temperature, water was added and the precipitated solid was collected by filtration and extracted with chloroform. The organic layer was washed with 30% potassium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:chloroform/methanol) and recrystallized from hydrous dimethylformamide to give the title compound (0.7 g), melting point: 195–200° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27](/[CH:28]=[CH:29]/[CH:30]=[O:31])=[C:26]([CH:32]([CH3:34])[CH3:33])[N:25]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:24]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:19][CH:18]=1>O1CCCC1.CCCCCC.O.C(O)(=O)C>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27](/[CH:28]=[CH:29]/[CH:30]([OH:31])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:26]([CH:32]([CH3:34])[CH3:33])[N:25]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[C:24]=2[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:19][CH:18]=1
Reactant: CC(C)c1c(/C=C/C=O)c(-c2ccc(F)cc2)c(-c2ccccc2)n1N1CCCC1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)c(-c2ccccc2)n(N2CCCC2)c1C(C)C
Reaction time: 0.25 h

Procedure:
1.1 ml (10 mmol) of methyl acetoacetate in 5 ml of dry tetrahydrofuran are added dropwise under nitrogen to a suspension of 360 mg (12 mmol) of 80% strength sodium hydride in 30 ml of dry tetrahydrofuran at -5° C. After 15 minutes, 6.2 ml (10 mmol) of 15% strength butyllithium in n-hexane are added dropwise at the same temperature and the mixture is subsequently stirred for 15 minutes. 2 g (5 mmol) of the compound from Example 4, dissolved in 20 ml of dry tetrahydrofuran, are subsequently added dropwise and the mixture is subsequently stirred for 30 minutes at -5° C. 3.3 ml of 50% strength acetic acid are cautiously added to the reaction solution, it is diluted with 100 ml of water and the mixture is extracted three times using 100 ml of ether each time. The combined organic phases are washed twice with saturated sodium hydrogen carbonate solution and once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 4:6).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24]([O:26]CC)=[O:25])([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C1(N2CCCCC2=O)CCNCC1)=O)C.C(OC(ON1C(=O)CCC1=O)=O)C1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:24]([OH:26])=[O:25])([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]2=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(N2CCCCC2=O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CCOC(=O)C1(N2CCCCC2=O)CCNCC1
Agent: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(N2CCCCC2=O)CC1
Reaction time: 1.5 h

Procedure:
1-Benzyloxycarbonyl-4-(ethoxycarbonyl)-4-(2-oxopiperidino)-piperidine. 4-(Ethoxycarbonyl)-4-(2-oxopiperidino)piperidine (9.0 g) in dichloromethane (25 mL) was added to a solution of N-(benzyloxycarbonyloxy)succinimide (8.8 g) and triethylamine (5.4 mL) in dichloromethane (150 mL). After 1.5 hours, the reaction mixture was washed successively with 1.0N hydrochloric acid and saturated aqueous sodium bicarbonate. The separated organic layer was dried and evaporated to give the title compound (11.6 g) as a light yellow solid; MS: m/z=389(M+1); NMR (CDCl3 /CF3COOH): 7.37 (m,5), 5.16 (s,2), 4.28 (q,2, J=7.1), 4.09 (m,2), 3.40 (m,2), 3.28 (m,2), 2.53 (m,2), 2.34 (m,2), 1.83 (m,6), 1.30 (t,3, J=7.1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2].CI.[CH2:27](I)[CH3:28]>>[CH2:1]([O:3][C:4]1[C:5]([O:22][CH2:23][CH3:24])=[CH:6][C:7]2[N:13]([CH2:27][CH3:28])[C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)[CH3:2]
Reactant: CCI
Reactant: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NCC(=O)N2
Solvent: CI
Product: CCOc1cc2c(cc1OCC)N(CC)C(=O)CN=C2c1ccccc1
Yield: 59 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-diethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIag), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 59%. M: 99–102° C. 1H-NMR (CDCl3, 300 MHz): d 1.11 (t, 3H, CH3), 1.36 (t, 3H, CH3), 1.53 (t, 3H, CH3), 3.93 (q, 2H, OCH2), 3.97 (AB system, ?d=0.67, JAB=14.0, 2H, —NCH2), 4.17 (q, 2H, OCH2), 4.28 (AB system, ?d=0.96 JAB=10.0, 2H, CH2), 6.68 (s, 1H Ar), 6.84 (s, 1H Ar), 7.38–7.64 (m, 5H Ar).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: CN(CCBr)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and tert-butyl 2-bromoethyl(methyl)carbamate using the method described in Example 41, followed by deprotection using trifluoroacetic acid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17].Cl.[NH2:44][OH:45]>O.C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C@@:15]([OH:42])([CH2:36][N:37]1[CH:41]=[N:40][CH:39]=[N:38]1)[C@H:16]([N:18]1[C:23](=[O:24])[C:22]2[S:25][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=[N:33][NH:44][OH:45])=[CH:30][CH:29]=3)=[CH:27][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: NO
Reactant: C[C@@H](n1cnc2cc(-c3ccc(C#N)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](n1cnc2cc(-c3ccc(C=NNO)cc3)sc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.1 %

Procedure:
To a solution of Na2CO3 (0.84 g, 7.92 mmol) in a mixture of H2O (8 mL) and THF (30 mL) was added (1R,2R)-4-[3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl]benzonitrile (0.5 g, 0.99 mmol, obtained in example 32) and hydroxylamine hydrochloride (0.35 g, 1.95 mmol). The mixture was stirred at reflux overnight, concentrated and the aqueous residue was extracted with CHCl3. The organic phase was separated, dried over Na2SO4, filtered and the filtrate concentrated to a solid which was purified by flash chromatography to give the title compound as a pale yellow solid (325 mg, 61%): mp 246°-247° C.; 1H NMR (300 MHz, MeOH-d4) δ (MeOH) 8.60 (s, 1H, N=CH--N), 8.18 (s, 1H, triazole), 7.86 (d, J=8.5, 2H, arom), 7.78 (d, J=8.5, 2H, arom), 7.71 (s, 1H, triazole), 7.66 (s, 1H, thiophene), 7.43 (dt, Jt =6.5, Jd =9, 1H, arom), 7.06 (ddd, Jd =2.5, Jd =8.5, Jd =14, 1H, arom), 6.89 (dt, Jd =2.5, Jt =8.5, 1H, arom), 6.09 (q, J=7.3, 1H, MeCH), 5.09 (d, J=14.2, 1H, CH(H)), 4.19 (d, J=14.2, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); MS 314 (N-ethylheterocycle, C15H14N4O2S), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =+74.9° (c 1, MeOH). Analysis calculated for C25H21F2N7O3S: C 55.86; H 3.94; N 18.24; S 5.96. Found: C 55.10; H 3.84; N 17.72; S 5.69.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[OH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](C(O)=O)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CCOCC>[C:11]([O:10][C:6]([C@H:19]1[CH2:20][CH2:21][C@H:16]([OH:15])[CH2:17][CH2:18]1)=[O:5])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](O)CC1
Temperature: 80 °C
Reaction time: 25 h

Procedure:
N,N-Dimethylformamide di-tert-butyl acetal (7.4 ml, 31 mmol) was added to a solution of trans-4-hydroxy-cyclohexanecarboxylic acid (1.484 g, 10.29 mmol) in toluene (8.5 ml), and the mixture was stirred at 80° C. for 25 hours. The reaction mixture was diluted with ether, and the organic layer was sequentially washed with water, an aqueous sodium bicarbonate solution and saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give trans-4-hydroxy-cyclohexanecarboxylic acid tert-butyl ester as a colorless solid (838 m, 41%).