Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C>CO.[C].[Pd]>[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:22][CH2:23][N:24]([CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH2:25][CH2:26]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
To 1-Boc-azetidin-3-on (1.00 g) and 4-(tert-butoxycarbonylamino)piperidine (1.17 g) dissolved in methanol (50 ml) were added acetic acid (0.368 ml) and 10% palladium carbon (1.0 g), followed by stirring under hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was stirred under hydrogen atmosphere (0.4 MPa) at room temperature for 4 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by partition. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated. The resultant crystals were suspended in diethyl ether-hexane, collected by filtration, and washed with hexane. There crystals were dried under aeration to provide the title compound (1.21 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][NH:31]C(OC(C)(C)C)=O)[CH:26]=[CH:27][C:28]=1[CH3:29].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:30]([C:25]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:23]([Cl:22])[CH:24]=3)[N:31]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: Cc1ccc(NNC(=O)OC(C)(C)C)cc1Cl
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)c(F)cc3Cl)[nH]c2=O)cc1Cl
Yield: 46.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.300 g), tert-butyl 2-(3-chloro-4-methylphenyl)hydrazinecarboxylate (Intermediate-87, 0.300 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16]Cl)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=[O:19].[Na+].[Na+].Cl>O.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][OH:19])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OC)c(CCl)c2)CC1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: COC(=O)C1(c2ccc(OC)c(CO)c2)CC1
Temperature: 65 °C
Yield: 43.1 %

Procedure:
To a suspension of crude 1-(3-chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (20.0 g) in water (350 mL) was added Bu4NBr (4.0 g) and Na2CO3 (90.0 g, 0.85 mol) at room temperature. The reaction mixture was heated at 65° C. overnight. The resulting solution was acidified with aq. HCl (2 mol/L) and extracted with EtOAc (200 mL×3). The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to give crude product, which was purified by column (Petroleum Ether/EtOAc 15:1) to give 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.0 g, 39%). 1H NMR (CDCl3, 400 MHz) δ 7.23-7.26 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 4.67 (s, 2H), 3.86 (s, 3H), 3.62 (s, 3H), 1.58 (q, J=3.6 Hz, 2H), 1.14-1.17 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:4]=[N:3]1.C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:9])=[O:10])[CH:4]=[N:3]1
Reactant: Cc1c(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cnn1C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cnn(C)c2C)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
tert-Butyl {[1-[(1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (290 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 178 mg, 71%).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([CH3:21])=[CH:9][C:10](=[O:20])[N:11]3[CH2:14][CH:15]3OCC[O:16]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O>[CH:1]1([C:4]2[CH:13]=[C:12]3[C:7]([C:8]([CH3:21])=[CH:9][C:10](=[O:20])[N:11]3[CH2:14][CH:15]=[O:16])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(=O)n(CC2OCCO2)c2cc(C3CC3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(=O)n(CC=O)c2cc(C3CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.10 g of 7-cyclopropyl-1-(1,3-dioxolan-2-ylmethyl)-4-methylquinolin-2(1H)-one, 3 mL of an 80% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 1 hour, and then stood still at room temperature for 13 hours. Thereto were added 3 mL of ethyl acetate and 4 mL of water, and the mixture was neutralized with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 59 mg of a light brown oily substance, (7-cyclopropyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)acetaldehyde.
Reaction SMILES: [Li].[CH3:2][C:3]1([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[F:15])[CH2:6][NH:5][C:4]1=O>C1COCC1>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2([CH3:2])[CH2:4][NH:5][CH2:6]2)=[C:9]([F:15])[CH:10]=1
Reactant: CC1(c2ccc(N)cc2F)CNC1=O
Agent: [Li]
Solvent: C1CCOC1
Product: CC1(c2ccc(N)cc2F)CNC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 106.8 %

Procedure:
A flame-dried 3-neck 2-L round bottom flask equipped with mechanical stirrer, reflux condenser, and addition funnel was charged with 300 mL tetrahydrofuran and 350 mL 1 M lithium aluminumhydride (0.35 mol) followed by cooling to 0° C. This solution was treated with a solution of 9.85 g 3-Methyl-3-(4-amino-2-fluorophenyl)-2-azetidinone (0.051 mol) in 210 mL THF with gas evolution and a yellow coloration. The cooling bath was removed and the reaction was heated to reflux with the rapid formation of a white precipitate. After 20 hours, the visually unchanged reaction mixture was cooled to room temperature and quenched by the successive addition of 13 mL water, 12 mL 5 M sodium hydroxide, and 47 mL water. The resulting thick gelatinous suspension was diluted with one L ethyl acetate, filtered through a pad of CELITE, concentrated, and high vacuum dried to afford 9.82 g of the title compound as a light orange syrup. 1H NMR (300 MHz, CDCl3) δ6.78 (t, 1H, J=8.5 Hz, aromatic), 6.37 (m, 2H, aromatic), 4.06 (d, 2H, J=8.2 Hz, N--CH2a s), 3.81 (bs, 3H, NHs), 3.58 (d, 2H, J=8.2 Hz, N--CH2b s), 1.65 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[C:13](C1NC=CN=1)(C1NC=CN=1)=[O:14]>ClCCl>[C:7]1([C@@H:2]2[C:3]([CH3:6])([CH3:4])[O:5][C:13](=[O:14])[NH:1]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(O)[C@H](N)c1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Yield: 82.2 %

Procedure:
To a solution of (13) (1.30 g, 7.89 mmol) in dichloromethane (100 ml) was added carbonyl diimidazole (1.534 g, 9.47 mmol) and the reaction mixture was refluxed for 2 hours. The reaction was quenched with hydrochloric acid (1M) and the product extracted repeatedly with dichloromethane. The combined organic extracts were dried over magnesium sulphate. After concentration in vacuo the residue was purified by flash column chromatography using 40% ethyl acetate/40-60 petroleum ether as eluant to give the title compound (15) (1.24 g, 82%).
Reaction SMILES: [CH:1]1([C:6]2[C:10]([N+:11]([O-])=O)=[C:9]([C:14]([NH2:16])=[O:15])[O:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>O.[Zn]>[NH2:11][C:10]1[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:7][O:8][C:9]=1[C:14]([NH2:16])=[O:15]
Reactant: NC(=O)c1onc(C2CCCC2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: NC(=O)c1onc(C2CCCC2)c1N
Temperature: 0 °C
Yield: 71.9 %

Procedure:
3.15 g (13.9 mmol) of 3-cyclopentyl-4-nitro-isoxazole-5-carboxamide (example V) and 17.51 g (327 mmol) of ammonium chloride are suspended in 70 ml of water and the suspension is cooled to 0° C. 8.5 g (118 mmol) of zinc powder are added in small portions while stirring vigorously. The reaction mixture is stirred at room temperature for 30 minutes. For the working up, filtration takes place through kieselguhr with the kieselguhr subsequently being washed with ethyl acetate, and the filtrate is evaporated to dryness in vacuo. The residue is triturated with ethyl acetate. After filtering, the solvent is removed in vacuo. 1.95 g (70%) of colorless solid are obtained.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:38])[F:37])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1.[BH3-][C:40]#N.[Na+].C(#N)C>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:37])[F:38])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][N:32]([CH3:40])[CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C(Nc1cn(CC=C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CN1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 1.2 %

Procedure:
An aqueous solution of 40% formaldehyde (210 mg) was added to solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(piperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (360.00 mg, 0.700 mmol) in methanol (30 mL). The resulting solution was stirred at ambient temperature for 2.5 h and NaBH3CN (44.02 mg, 0.700 mmol) was added. The resulting solution was stirred at this temperature for 3 h and concentrated under vacuum. The residue was applied onto a short pad of silica gel eluting with dichloromethane/MeOH (10/1). The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/10 mmol NH4HCO3=40% increasing to ACN/10 mmol NH4HCO3=75% within 6 min; Detector, UV 254 nm to obtain 4.3 mg (1%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1-methylpiperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 32): [M+H]+=528.1, RT=2.21 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m, 2H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.44 (t, 1H, J=6.8 Hz), 4.27 (d, 2H, J=6.8 Hz), 2.81-2.68 (m, 2H), 2.52-2.50 (m, 2H), 2.50-2.42 (m, 2H), 2.19 (s, 3H), 2.12-2.04 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[F:14][C:15]([F:27])([F:26])[C:16]([NH:18][C@@H:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17]>>[CH:8]1([CH2:7][N:6]2[C:2]([N:22]3[CH2:23][CH2:24][CH2:25][C@@H:19]([NH:18][C:16](=[O:17])[C:15]([F:26])([F:14])[F:27])[CH2:20][CH2:21]3)=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=[N:5]2)[CH2:10][CH2:9]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(CC2CC2)c1Cl
Product: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1)C(F)(F)F
Yield: 55 %

Procedure:
Following the procedure for Example 503 starting with 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and (R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave (R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow gum (0.98 g, 55%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 6.42-6.39 (m, 1H), 4.22-4.14 (m, 1H), 4.00-3.85 (m, 2H), 3.44-3.32 (m, 1H), 3.30-3.15 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H), 1.30-1.20 (m, 1H), 0.70-0.62 (m, 2H), 0.50-0.35 (m, 2H).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Cl-].[Zr+4:5].[Li+:6].[Li+:7].[Li+:8].[NH2-:9]>>[N:9]([Li:8])([Li:7])[Li:6].[Cl-:1].[Cl-:1].[Cl-:1].[Cl-:1].[Zr+4:5]
Reactant: [NH2-]
Reactant: [Li+]
Agent: [Zr+4]
Agent: [Cl-]
Product: [Li]N([Li])[Li]

Procedure:
A mortar and pestle was used to mix 0.991 gram of zirconium tetrachloride (ZrCl4) and 0.204 gram of lithium nitride (Li3N) in order to form the reactant mixture with a stoichiometric ratio of Li3N to ZrCl4 of 4/3. The reactant mixture was placed in a 45 milliliter stainless steel container. A screw top cap was placed on the stainless steel container. The screw top cap had two insulated leads protruding therethrough, which held a nichrome filament in the reactant mixture. An external electric charge was applied to the leads for no more than two seconds thereby igniting the reactant mixture. The resulting brown product was washed with methanol, dried and then ground with a mortar and pestle. The product was further washed with ten percent nitric acid, water and acetone on a vacuum filter. The powder was then dried on a vacuum line. The resulting product was pure ZrN with a cubic lattice spacing of 4.57 Angstroms as determined by X-ray powder diffraction. Use of the Scherrer equation gave a calculated particle size of 200-250 Angstroms. See Elements of X-ray Diffraction written by B. D. Cullity, Addison-Wesley, Reading, Mass., 1956. The product yield was fifty five percent (0.2488 gram out of 0.4475 gram theoretically possible). A pressed disc indicated metallic type conductivity. A balanced equation is as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:26]3[C:17]4=[N:18][N:19]([CH3:25])[C:20]5[CH:21]=[CH:22][C:23](Cl)=[C:15]([C:16]=54)[C:14](=[O:27])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:26]3[C:17]4=[N:18][N:19]([CH3:25])[C:20]5[CH:21]=[CH:22][C:23]([NH:34][CH2:33][CH2:32][N:31]([CH3:35])[CH3:30])=[C:15]([C:16]=54)[C:14](=[O:27])[C:13]=3[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2cncc3c2-c2nn(C)c4ccc(Cl)c(c24)C3=O)cc1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: COc1ccc(COc2cncc3c2-c2nn(C)c4ccc(NCCN(C)C)c(c24)C3=O)cc1
Reaction time: 3 h

Procedure:
A solution of 10-(p-methoxybenzyloxy)-5-chloro-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one of Example 11 (0.053 g) and N,N-dimethylethylenediamine (0,115 g) in pyridine (0.5 mL) is heated at 120° C. for 3.5 h under a nitrogen atmosphere. The excess diamine and pyridine are removed by a slow stream of nitrogen gas and the resultant dark orange residue is placed under vacuo for 3 h. The crude material is purified by radial chromathography (silica gel, 2 mm thickness) using gradient elution commencing with 2% methanol/98% chloroform (100 mL) to mixtures containing 4% methanol (75 mL) to 6% methanol (60 mL). Upon removal of the 4% methanol (96% chloroform eluent, starting material is recovered (10 mg). Removal of the 6% methanol/94% chloroform eluent led to 10-p-methoxybenzyloxy-5-[[2-(dimethylamino)ethyl]amino]-2-methylisoquino[5,6,7-cd]indazole-6(2H)-one as a pure product (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][NH:14][CH3:15])[CH2:6]2.Br[CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH2:17][C:18]#[N:19])[CH3:15])[CH2:6]2
Reactant: CNC[C@H]1Cc2cc(OC)c(OC)cc21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CC#N)C2
Reaction time: 8 h

Procedure:
At ambient temperature, 1.04 g (5 mmol) of {[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}methylamine, 0.35 mL (5 mmol/1 eq.) of bromoacetonitrile and 2.16 g (20 mmol/4 eq.) of sodium carbonate are mixed into 16 mL of methyl isobutyl ketone. Refluxing is carried out overnight, followed by drying. The residue is taken up in water and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulphate to yield, after concentration, the expected product.
Reaction SMILES: C1(C(Cl)=O)CCCC1.C1(C(Cl)=O)CCCCC1.[C:18]([NH:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])=[C:28]([O:40][C:41]([CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[CH:27]=1)=[O:25])([CH3:21])([CH3:20])[CH3:19]>>[CH:43]1([C:41]([O:40][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=2[O:32][C:33]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:34])[CH:24]([OH:25])[CH2:23][NH:22][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:42])[CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C2CCCC2)c(OC(=O)C2CCCC2)c1
Agent: O=C(Cl)C1CCCC1
Agent: O=C(Cl)C1CCCCC1
Product: CC(C)(C)NCC(O)c1ccc(OC(=O)C2CCCC2)c(OC(=O)C2CCCC2)c1

Procedure:
When cyclopentanecarbonyl chloride is substituted for the cyclohexanecarbonyl chloride in the procedure described in Example 15A above, the acylation product obtained is 3,4-bis(cyclopentanecarbonyloxy)phenyl tert-butylaminomethyl ketone; and when this product is catalytically hydrogenated using the procedure described in Example 15B above, there is obtained 3,4-bis(cyclopentanecarbonyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol.
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH2:10]1)=O)C.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:6]([C:23]([O:22][CH2:20][CH3:21])=[O:28])=[C:5]([CH3:4])[NH:27][C:25]=1[NH2:26])=[O:28])[CH3:21]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)CC(=O)C=C1CC=Cc2ccccc21
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 62 %

Procedure:
Boiling a solution of 13.4 g of (1-naphthylidene)acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours yields 2-amino- 6-methyl-4-(1-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 174° C. (ethanol).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C(OP(CC(OCC)=O)(OCC)=O)C.C(O[K])(C)(C)C.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>O1CCCC1>[CH2:39]([O:38][C:35](=[O:37])[CH2:36][CH:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)[CH3:2])[CH3:40]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CCOC(C)=O
Agent: CC(C)(C)O[K]
Agent: CCOC(=O)CP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 4-acetylbenzate (5.00 g, 26.0 mmol) was added to a solution (130 ml) of ethyl diethylphosphonoacetate (6.71 ml, 33.8 mmol) and tert-butoxy potassium (4.38 g, 39.0 mmol) in tetrahydrofuran at 0° C., and the mixture was stirred at room temperature for 16 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate). The mixture of the obtained oil and 10% palladium carbon (1 g) in ethanol (150 ml) was stirred under a hydrogen atmosphere for 2 hrs, and filtered through celite. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (5.67 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#Cc1c(N)cccc1OC1CCCCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cycloheptyloxy)benzonitrile (Example 32b) and ethyl 3-oxobutanoate as a bright yellow solid (72%). 1H NR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 1.49-1.65 (m, 8H), 1.78-1.87 (m, 2H), 2.04-2.10 (m, 2H), 2.53 (s, 3H). 4.31 (q, J=8.0 Hz, 2H), 4.79 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 8.14 (brs, 2H). MS 343 (MH+).
Reaction SMILES: [ClH:1].C([N:5]1[CH2:10][CH2:9][C:8]2[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([NH2:14])[C:7]=2[CH2:6]1)(=O)C>CO>[ClH:1].[NH2:14][C:13]1[C:7]2[CH2:6][NH:5][CH2:10][CH2:9][C:8]=2[S:11][C:12]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1sc2c(c1N)CN(C(C)=O)CC2
Agent: Cl
Solvent: CO
Product: COC(=O)c1sc2c(c1N)CNCC2
Yield: 68 %

Procedure:
20 ml of methanol and then 5.1 ml of concentrated hydrochloric acid were added to 2.54 g of methyl 5-acetyl-3-amino-4,5,6,7tetrahydrothieno[3,2-c]pyridine-2-carboxylate (Compound No. 16) obtained in Example 1. The resultant mixture was heated under reflux for 4 hours. After cooling, the crystals thus formed were taken by filtration to obtain 1.70 g (68%) of methyl 3-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate hydrochloride.