Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>C1COCC1>[CH:3]1([N:2]([CH3:1])[C:22](=[O:23])[C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCCC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To an ice cold stirred solution of N-methylcylohexylamine (20 ml, 0.15 mol) and triethylamine (22 ml) in dry THF (100 ml) under argon was slowly added p-toluoyl chloride (20 ml, 0.15 mol). A white precipitate formed. The ice bath was removed and the mixture stirred at ambient temperature for 24 h. Ice cold 2M hydrochloric acid (100 ml) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine (3×100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give the crude amide, which was crystallised from hexane to give N-cyclohexyl-N-methyl-4-methylbenzamide (30.9 g, 87%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[CH2:7][C:6]=2[CH:16]=1.[N+:17]([O-])([OH:19])=[O:18].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:10])[CH2:7][C:6]=2[CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C1(C)Cc2cc(Cl)ccc2O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C1(C)Cc2cc(Cl)cc([N+](=O)[O-])c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Stirred concentrated sulfuric acid, 50 mL, was cooled in an ice-water bath, and 9.0 grams (0.037 mole) of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran was added. To this solution was added dropwise a solution of 2.6 grams (0.041 mole) of 90% nitric acid in 2 mL of concentrated sulfuric acid, while maintaining the reaction mixture temperature at 10°-16° C. Upon completion of the addition, the reaction mixture was stirred at the ice-water bath temperature for 30 minutes, then allowed to warm to ambient temperature where it stirred for one hour. The reaction mixture was poured into ice and neutralized with sodium bicarbonate and extracted with three portions of methylene chloride. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel, with 3:7 ethyl acetate:heptane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methyl- 7-nitrobenzofuran, mp 69°-72.5° C. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH2:24][CH2:23]1>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH2:30][C:31]([O:1][CH2:2][C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]3)=[CH:5][CH:4]=2)=[O:32])[CH2:26][CH2:27]1
Reactant: COc1ccccc1N1CCN(CCCC(=O)O)CC1
Reactant: O=C1CCc2ccc(CO)cc2N1
Product: COc1ccccc1N1CCN(CCCC(=O)OCc2ccc3c(c2)NC(=O)CC3)CC1

Procedure:
(2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl 4-(4-(2-methoxyphenyl)piperazin-1-yl)butanoate (38c) (Scheme 7) was prepared from the carbinol 37 and the carboxylic acid 18c according to the protocol described for the compound 38a (Example 55). Colorless oil, 0.15 g (41%). 1H NMR (400 MHz, CDCl3): δ 1.84 (quintet, J=7.2 Hz, 2H); 2.38-2.54 (m, 4H); 2.58-2.60 (m, 6H); 2.95 (t, J=8.4 Hz, 2H); 3.03 (broad s, 4H); 3.80 (s, 3H); 5.02 (s, 2H); 6.80-6.94 (m, 4H); 7.09 (d, J=7.6 Hz, 1H); 9.30 (m, 1H). MS (ESI): m/z=438.20 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9](=[N:11][NH2:12])[NH2:10])=[N:6][C:7]=1[CH3:8].[CH:13](O)=O>>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9]2[N:10]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1nc(C(N)=NN)ccc1Br
Product: Cc1nc(-c2nc[nH]n2)ccc1Br
Temperature: 100 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A 500-mL, three-neck, round-bottom flask was equipped with a mechanical stirrer, a thermocouple connected to a J-KEM temperature controller and a reflux condenser. The flask was charged with 5-bromo-6-methylpicolinohydrazonamide (100 g, 0.463 mol) and formic acid (250 mL). The resulting solution was heated to 100° C. and stirred for 48 h. Formic acid was removed under reduced pressure and the resulting slurry was treated with water (1.5 L) while vigorously stirring. The mixture was filtered and washed with water (300 mL). The solids were transferred into a round-bottom flask and treated with water (1 L) and 1 M sodium hydroxide solution until pH 7. The mixture was allowed to stir for 30 min, filtered, washed with water (300 mL) and dried in a vacuum oven at 30-35° C. for 48 h to afford the product (96 g, 92% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:30]2[CH:42]=[CH:41][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:32][CH:31]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:30]2[CH:31]=[CH:32][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:41][CH:42]=2)[CH:3]=1)[CH3:21]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 88 °C
Reaction time: 1 h
Yield: 164 %

Procedure:
A mixture of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (580 g, 1.63 mol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (592 g, 1.95 mol), 1,4-dioxane (3.86 L), sodium carbonate (618 g, 5.83 mol), and water (771 ml) was degassed by bubbling nitrogen through the mixture at 20° C. for 20 minutes and treated with tetrakis(triphenylphosphine)palladium(0) (14.11 g, 12.21 mmol). The resulting mixture was degassed for an additional 20 minutes and then heated to 87-89° C. for 17 h. After cooling to 20° C., the mixture was diluted with ethyl acetate (5.80 L) and a solution of (R)-2-Amino-3-mercaptopropionic acid (232 g) in water (2.320 L). After stirring for 1 h at 20° C., the organic layer was separated and washed again with a solution of (R)-2-Amino-3-mercaptopropionic acid (232 g) in water (2.320 L). The aqueous layers were combined and extracted with ethyl acetate (5.80 L). The organic layers were combined, washed with a solution of sodium hydroxide (93 g) in water (2.32 L), and concentrated under vacuum at 35° C. to give the title compound as an orange oil (1.21 kg, 164% yield).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:19][C:20]1[CH:21]=[N:22][N:23]2[C:28]3[N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][C:27]=3[C:26]([CH3:34])=[N:25][C:24]=12>C1C=CC=CC=1>[Br:19][C:20]1[CH:21]=[N:22][N:23]2[C:28]3[N:29]([CH2:32][CH3:33])[CH:30]=[CH:31][C:27]=3[C:26]([CH3:34])=[N:25][C:24]=12
Reactant: CCN1CCc2c(C)nc3c(Br)cnn3c21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCn1ccc2c(C)nc3c(Br)cnn3c21
Reaction time: 2 h
Yield: 41.1 %

Procedure:
2.16 g (8.92 mmoles) of benzoyl peroxide were added to a solution of 2.50 g (8.89 mmoles) of 3-bromo-7,8-dihydro-8-ethyl-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (prepared as described in Example 8) dissolved in 30 ml of benzene, and the mixture was stirred for 2 hours. At the end of this time, the reaction mixture was washed with a 5% v/v aqueous solution of sodium bicarbonate and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with choloroform) and recrystallized from diisopropyl ether to afford 1.019 g (yield 41%) of the title compound as light yellow needles, melting at 113°-114° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([Cl:15])=[O:10])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cncc([N+](=O)[O-])c1
Product: O=C(Cl)c1cncc([N+](=O)[O-])c1

Procedure:
A mixture of 2 g of 5-nitronicotinic acid and 30 ml. of thionyl chloride was refluxed for 3 hours. Excess thionyl chloride was distilled off to give oily 5-nitronicotinoyl chloride. The acid chloride thus obtained was added to 10 ml of pyridine at -15° C. and 1.4 g of 2-thiophene carboxamide was added thereto. The resulting mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure at a temperature below 40° C. and the residue was purified over silica gel chromatography and recrystallized from ethyl acetate-n-hexane to give 200 mg of the desired product. mp 187° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:5][CH2:4]1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>O.C(O)C>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[CH2:18][O:19]3)=[CH:12][CH:13]=2)[CH2:4][CH2:5]1
Reactant: Oc1ccc(OCC2CC2)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1cc(OCC2CO2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.46 g of sodium hydroxide in 1.8 ml water and 14 ml ethanol, 1.64 g of p-(cyclopropylmethoxy)-phenol and 5.54 g of epichlorohydrin is stirred at room temperature in a nitrogen atmosphere for 24 hours and left at room temperature for 21/2 days. The solvent is evaporated in vacuo and the residue is taken up in ether, washed with water and sodium chloride solution. After drying over anhydrous magnesium sulfate, the solution is filtered and concentrated under reduced pressure to yield p-(cyclopropylmethoxy)-phenoxymethyloxirane which is used directly in the condensation.
Reaction SMILES: C([O:8][C:9](=[O:54])[CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[C:31]3[C:23](=[CH:24][C:25]4[CH2:26][O:27][CH2:28][C:29]=4[CH:30]=3)[C@@H:22]([N:32]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=3)[C:33]3[N:34]=[N:35][N:36]([CH3:38])[N:37]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:12]1)C1C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[F:53][C:50]([F:51])([F:52])[C:42]1[CH:41]=[C:40]([CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=1)[CH2:39][N:32]([C:33]1[N:34]=[N:35][N:36]([CH3:38])[N:37]=1)[C@@H:22]1[C:23]2=[CH:24][C:25]3[CH2:26][O:27][CH2:28][C:29]=3[CH:30]=[C:31]2[N:18]([CH2:17][CH:14]2[CH2:15][CH2:16][CH:11]([CH2:10][C:9]([OH:54])=[O:8])[CH2:12][CH2:13]2)[CH2:19][CH2:20][CH2:21]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CC3CCC(CC(=O)OCc4ccccc4)CC3)c3cc4c(cc32)COC4)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CC3CCC(CC(=O)O)CC3)c3cc4c(cc32)COC4)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyclohexyl)-acetic acid benzyl ester (0.07 mmol) in methanol (5 mL), add NaOH (3 mL of 5N) and heat to 60° C. for 2 h. After cooling to room temperature, dilute with water (20 mL) and neutralize using 5 M HCl. Extract the organic phase using ethyl acetate (3×10 mL). Dry the combined organics over sodium sulfate, filter, and remove solvent under vacuum, to provide the title compound as a colorless foam. MS (ES+): 667 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29](I)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C(O)C.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(-c4ccc(F)cc4)c(-c4ccccc4Cl)nn23)CC1
Temperature: 80 °C
Yield: 266 %

Procedure:
A mixture of 1-[7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1i; 20 mg, 0.037 mmol) and 4-fluorophenylboronic acid (7.8 mg, 0.056 mmol) in ethanol (1.3 ml), toluene (1.3 ml) and 2M aqueous Na2CO3 (0.3 ml) was degassed (3×) by pulling a vacuum followed by refilling with nitrogen gas. Tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) was added and the mixture was heated at 80° C. for 5 hours. After cooling to room temperature, the mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-3% methanol in methylene chloride as eluant afforded a light yellow oil, which was crystallized from diethyl ether, and dried, in vacuo, to afford 1A-1 (11 mg, 58%) as a colorless solid: +ESI MS (M+1) 508.4; 1H NMR (400 MHz, CD3OD) δ 7.46-7.34 (m, 4H), 7.32 (dd, J=8.7, 5.4 Hz, 2H), 6.96 (t, J=8.7 Hz), 4.70-4.58 (br m, 2H), 4.40-4.25 (br m, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.46 (s, 3H), 2.20-2.12 (br m, 2H), 1.83-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+]>>[C:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:25][CH:24]=1)#[N:33]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 95.3 %

Procedure:
Following a procedure similar to that as described in Example 68(a), but using 4.01 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9), 5.0 g of 4'-bromomethylbiphenyl-2-carbonitrile and 1.97 g of potassium t-butoxide, 6.86 g of the title compound were obtained as crystals, melting at 92°-93° C.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([N:20]2[CH2:6][CH2:5][N:4]([C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]4)=[O:8])[CH2:3][CH2:2]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCc2cc(C(=O)N3CCOCC3)ccc2N1
Reactant: Nc1ccccc1
Product: O=C1CCc2cc(C(=O)N3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.62 Grams of 6-morpholinocarbonyl-3,4-dihydrocarbostyril and 10 g of aniline were placed in a sealed tube and heated at 170°-200° C. for 5 hours. Excess aniline was removed by evaporation under reduced pressure, then the residue thus obtained was purified by means of silica gel column chromatography. Recrystallized from isopropanol to obtain 0.32 g of 6-(4-phenyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril. Colorless needle-like crystals. Melting point: 200°-201° C.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]Cl>C(OCC)(=O)C>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
N,N-Dimethylformamide (2.5 ml) was added to 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassium carbonate (0.081 g) and 2-dimethylaminoethyl chloride hydrochloride (0.078 g) followed by stirring at 80° C. overnight (12 hr). After allowing to cool, the resultant mixture was mixed with ethyl acetate (200 ml) and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.052 g) as a brown oil (yield: 27.0%).
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[N:5]=[C:6]2[CH:12]=[N:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]2=[N:8][CH:9]=1>C1(O)C=CC=CC=1.C(Cl)(Cl)Cl>[O:1]([C:4]1[N:5]=[C:6]2[CH:12]=[N:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]2=[N:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cnc2c(cnn2-c2ccccc2)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(Oc2cnc3c(cnn3-c3ccccc3)n2)cc1
Temperature: 150 °C
Yield: 92 %

Procedure:
In 5.0 (0.053 mole) of phenol was dissolved 0.34 g (0.0085 mole) of sodium hydroxide, and 1.00 g (0.0043 mole) of 5-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was maintained at 150° C. for 2 hours. The reaction mixture was dissolved in chloroform, and the resulting solution was washed with an aqueous 10% solution of sodium hydroxide and then dried. The solvent was removed by distillation, and the residue was recrystallized from a benzene-hexane mixed solvent to obtain 1.20 g (the yield was 92%) of 5-phenoxy-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless needle crystal.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[CH:11]=[CH:12][C:13](=[O:15])[CH3:14].[C:16]12([CH3:26])[C:23]([CH3:25])([CH3:24])[CH:20]([CH2:21][CH2:22]1)[CH2:19][C:17]2=O.[OH-].[K+].Cl>CO>[CH3:26][C:16]12[C:23]([CH3:25])([CH3:24])[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:17]2[CH2:14][C:13](=[O:15])[CH2:12][CH2:11][CH:3]1[C:4]([CH3:9])([CH3:10])[CH:5]2[CH2:8][C:2]1([CH3:1])[CH2:7][CH2:6]2
Reactant: CC(=O)C=CC1C2(C)CCC(C2)C1(C)C
Reactant: CC12CCC(CC1=O)C2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC12CCC(C1)C(C)(C)C2CCC(=O)CC1CC2CCC1(C)C2(C)C
Temperature: 20 °C
Reaction time: 6 h

Procedure:
20.6 gm. (0.1 mole) of 1-(1,3,3-trimethylbicyclo-[2.2.1]hept-2-yl)-1-buten-3-one and 18.3 gm. (0.12 mole) of camphor is dissolved in 25 ml. methyl alcohol. A solution of 3.4 gm. of potassium hydroxide in 20 ml. of methyl alcohol is then added over a period of 15 minutes using good agitation and external cooling. The reaction mixture is maintaned at 40° C.-45° C. for 6 hours, cooled to 20° C., made slightly acid by the addition of dilute hydrochloric acid and the residue after solvent stripping under reduced pressure extracted with ether. The ether solution is washed two times with one-tenth its volume of cold water, dried over anhydrous magnesium sulfate and stripped of solvent under reduced pressure. The residual oil which contained 1-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-4-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)but-3-en-2-one is dissolved in 100 ml. of thiophene-free benzene and shaken under 50 psi hydrogen pressure in the presence of 3 gm. 5% palladium on carbon at 25° C. until slightly more than theoretical hydrogen uptake is observed. The catalyst is removed by filtration and the solvent stripped. The residual oil is purified by fractional distillation under reduced pressure to provide the 1-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-4-(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)butan-2-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.[ClH:14].[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.Cl>O1CCOCC1>[ClH:14].[C:15]1([CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccccc1N1CCN(Cc2ccc(CC(=O)O)cc2)CC1
Yield: 52.7 %

Procedure:
Using 2.2 g of methyl 4-bromomethylphenylacetate, 1.9 g of 1-(2-tolyl)piperazine hydrochloride, 2.5 ml of triethylamine, and 80 ml of dioxane, the reaction procedure of Example 2 was otherwise repeated and the reaction product was converted to the hydrochloride using 2N-hydrochloric acid and recrystallized from ethanol-ether to provide 1.7 g of the title compound melting at 249° C.-252° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:15]1[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=1.O>ClC(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:1][NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[N:20]=1
Reactant: CCOC(=O)N1CCC(NC)CC1
Reactant: CN(C)c1ccnc(Cl)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(NCc2nccc(N(C)C)n2)CC1
Temperature: 120 °C
Yield: 60.2 %

Procedure:
A mixture of ethyl 4-(methylamino)-1-piperidinecarboxylate (111.75 g) and 2-chloro-N,N-dimethyl-4-pyrimidinamine (47.3 g) is stirred and heated in an oil-bath for 22 hours at 120° C. The reaction mixture is cooled and the product is taken up in trichloromethane (500 ml). Water (300 ml) is added and the layers are separated. The organic phase is washed with water (200 ml), dried, filtered and evaporated. The residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from diisopropyl ether (390 ml). After cooling to 0° C., the product is filtered off and dried, yielding 55.5 g (59.7%) of ethyl 4-[[4-dimethylamino-2-pyrimidinyl]methylamino]-1-piperidinecarboxylate (intermediate 1).