Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K6) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (330 mg).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[C:14]([CH3:16])([CH3:15])[C:13]2([Cl:18])[Cl:17])(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:13]1([Cl:17])[C:14]([CH3:15])([CH3:16])[CH:12]1[CH2:11][C:20]#[N:21]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2C(C)(C)C2(Cl)Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(CC#N)C1(Cl)Cl
Temperature: 100 °C
Yield: 106.5 %

Procedure:
6.48 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl p-toluenesulfonate and 2.0 g of potassium cyanide were suspended in 20 ml of dimethyl formamide, and the mixture was heated at 100° C. for 24 hours with stirring. After cooling, 50 ml of water was added to the reaction mixture. The mixture was extracted with hexane. The hexane layer was washed with water, and dried over sodium sulfate. After drying, the hexane was evaporated under reduced pressure to give 3.8 g of 2,2-dichloro-3,3-dimethylcyclopropylacetonitrile, the desired compound shown above. The boiling point of the product was 96° to 98° C. at 14 mmHg.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]1([CH:12]([O:19][C:20](=[O:59])[CH:21]([N:25]2[CH:28]([S:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:27]([NH:40][C:41](=[O:57])[CH:42]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]2=[O:58])[C:22](=[CH2:24])C)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CSC>C(Cl)Cl>[C:6]1([CH:12]([O:19][C:20](=[O:59])/[C:21](/[N:25]2[CH:28]([S:29][S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:31])=[O:32])[CH:27]([NH:40][C:41](=[O:57])[CH:42]([NH:49][C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]2=[O:58])=[C:22](\[OH:4])/[CH3:24])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.12 h

Procedure:
An ozone/oxygen stream (0.5 mmol per minute) is passed for 7 minutes into a solution, cooled to -70° C., of 2.30 g (3.0 mmols) of 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride. After adding 1 ml of dimethyl sulphide, the solution is stirred for a further hour without cooling and is then concentrated by evaporation in vacuo. The residue is recrystallised from methylene chloride/ether/hexane and gives 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester of melting point 182°-184° C.; UV spectrum (ethanol): λmax =259 mμ (ε=13,400); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.59, 5.83, 5.92, 6.03 (shoulder), 6.18 and 6.68μ; thin layer chromatogram: Rf value~0.55 (silica gel; toluene/ethyl acetate, 1:1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14]C1(C)CCC2C(C)(C)C2(C2C=CC(C=O)=CC=2)C1=O.[S:34]1[CH2:38][C:37](=[O:39])[NH:36][C:35]1=[O:40].[C:41]([O-:44])(=O)[CH3:42].[Na+]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][NH:14][C:41](=[O:44])[C:42]1[CH:11]=[CH:12][C:7]([CH:5]=[C:38]2[S:34][C:35](=[O:40])[NH:36][C:37]2=[O:39])=[CH:8][CH:9]=1
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)[O-]
Reactant: Cc1oc(-c2ccccc2)nc1CNC1(C)CCC2C(C)(C)C2(c2ccc(C=O)cc2)C1=O
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1CNC(=O)c1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[(5-Methyl-2-phenyl-4-oxazolyl)methylaminocaronyl]benzaldehyde (0.880 g, 2.75 mmol), thiazolidine-2,4-dione (0.483 g, 4.12 mmol) and sodium acetate(0.676 g, 8.24 mmol) were intimately mixed and heated at 140°-145° C. for 45 minutes, then cooled to room temperature, the solids triturated and stirred with mL of water for 30 minutes and 1.20 g of present title product recovered by filtration; mp 235°-237° C. (dec); tlc Rf 0.2 (3:1 ethyl acetate:hexane).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1.C(O)C>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Yield: 81.9 %

Procedure:
A mixture of 2-acetylamino-5-formylpyridine (241 mg) and malonic acid (168 mg) in pyridine (0.12 ml) and ethanol (0.36 ml) was refluxed for 2 hours. After cooling the mixture, the precipitate was collected by filtration, and washed with ethyl acetate to give (E)-3-(6-acetylamino-3-pyridyl)acrylic acid (248 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH2:15].[Cl:16][C:17]1[S:21][C:20]([CH:22]=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:22][C:20]1[S:21][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: NCCCc1ccc2ccccc2c1Cl
Product: Clc1ccc(CNCCCc2ccc3ccccc3c2Cl)s1
Yield: 78 %

Procedure:
Prepared from 3-(1-chloronaphthalen-2-yl)propan-1-amine and 5-chlorothiophen-2-carbaldehyde in 78% yield as a red oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH:8]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:10]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[CH:8]=[C:9]([C:11](=[O:17])[N:12]([CH3:16])[CH2:13][CH2:14][CH3:15])[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(-c2ccccc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Chill a solution of 2′-fluoro-5-(methyl-propylcarbamoyl)-biphenyl-3-carboxylic acid methyl ester (0.297 g, 0.903 mmol) in MeOH (2 mL) and THF (2 mL) in an ice bath. Add 2 N NaOH (1.35 mL, 2.70 mmol) to the mixture and stir at room temperature for 3 h. Acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and H2O and extract the aqueous layer with ethyl acetate (2×15 mL). Wash the combined organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@@H]2CCCC[C@@H]2c2ccccc2)cc1F
Yield: 112.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (53.0 mg, 0.088 mmol) prepared in Example 3a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (44.6 mg, 99%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[CH2:46]O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:46][C:45]4[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=4[F:43])[CH:14]=3)=[CH:12][C:7]=2[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Reactant: OCc1ccccc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(OCc4ccccc4F)c3)cc21
Reaction time: 1 h

Procedure:
An orange solution of 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-179, 70 mg, 0.23 mmol) in Dichloromethane (10 ml) was treated with polymer bound-Triphenylphosphine (177 mg, 0.68 mmol, 3.0 eq) and the 2-Fluorobenzyl alcohol (56.9 mg, 0.45 mmol, 2.0 eq). The mixture was charged, in portions, with Di-tert-butyl azodicarboxylate (104 mg, 0.45 mmol, 2.0 eq) and the resulting maroon-orange solution was stirred at 23 deg C. for 1 h. The reaction mixture was filtered through a frit and the filtrate was purified via flash column chromatography (SiO2: 100% Hex to 75:25% Hex:EtOAc) to afford the title compound, 1-(2,2-dimethylpropyl)-5-{3-[(2-fluorobenzyl)oxy]phenyl}-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (3-1), as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (t, 1H, J=7.0 Hz), 7.38-7.26 (m, 3H), 7.22-7.15 (m, 3H), 7.13-7.06 (m, 3H), 6.97 (d, 1H, J=7.1 Hz), 5.21 (s, 2H), 3.68 (s, 2H), 3.47 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C26H27FN2O2 (M+H) 419.2, found 419.3.
Reaction SMILES: [OH2:1].[CH3:2][C:3]1([CH3:12])[NH:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:11])=N1.CC(C)=[O:15]>CO>[OH2:15].[CH3:2][C:3]1([CH3:12])[CH2:11][C:5](=[O:1])[CH2:6][C:7]([CH3:10])([CH3:9])[NH:8]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1

Procedure:
A mixture of 250 g of 2,2,4,4,6-pentamethyl-2,3,4,5-tetrahydropyrimidine hydrate, 100 g of acetone and 100 g of methanol is refluxed for 13 hours. The solution is subsequently concentrated in vacuo, and the oil remaining is distilled in vacuo. The yield is 185 g of a slightly yellowish oil, B.P.12 = 80°- 86°C, which, after the addition of about 22 ml of water, solidifies to form crystals of 2,2,6,6-tetramethyl-4-oxopiperidine-hydrate.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([O:1][CH:2]1[CH2:5][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1)(=[O:19])=[O:18]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(C(=O)OCC)CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
A solution of diethyl 3-hydroxy-1,1-cyclobutanedicarboxylate (0.268 g, 0.00116 mol) in pyridine (7 mL) was cooled to 0° C. Methanesulfonyl chloride (0.11 mL, 0.160 g, 0.00140 mol) was added dropwise, keeping the temperature below 2° C. The mixture was stirred for four hours, and then poured into ice water (20 mL) and extracted with ethyl ether (2×10 mL). The combined organic layers were washed with water (3×10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give diethyl 3-[(methylsulfonyl)oxy]-1,1-cyclobutanedicarboxylate (0.302 g, 0.00102 mol) as a yellow oil.:
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12](Cl)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CCOCC>[C:12]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NCCCCCC(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCC(=O)NCCCCCC(=O)O
Yield: 90.2 %

Procedure:
A one L beaker was charged with 250 mL of 1N sodium hydroxide solution (0.25 mol) and 32.8 g (0.25 mol) of 6-aminocaproic acid. The resulting solution was cooled in an ice bath and, with stirring, a solution of lauroyl chloride (54.7 g, 0.25 mol) in 100 mL ether was added dropwise while maintaining the pH of the stirred solution between 10 and 12 by addition of 10% sodium hydroxide solution. Addition of the lauroyl chloride required 45 min. During this period the reaction mixture became thick with solid and additional volumes of water and ether were added in order to keep the mixture stirrable. Following completion of the lauroyl chloride addition, the ice bath was removed and the mixture was stirred for 1.5 hr. at room temperature. The mixture was then adjusted to pH 2 with concentrated HCl, and the precipitate which formed was removed by filtration and washed with water. The resulting solid was slurried with hexane (200 ml), filtered, and washed 5 times with 100 ml portions of hexane. This hexane slurry/wash procedure was repeated a second time. The resulting solid was air dried to yield 70.7 g (90%) of N-lauroyl-6-aminocaproic acid, mp 87°-90° C. [lit mp 85°-86° C.--E. Jungerman, J. F. Gerecht, and I. J. Krems, J. Amer. Chem. Soc., 78, 172 (1956).]
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:17])=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:18]=[C:19]([CH3:21])[CH:20]=[C:4]2[N:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CN(C)CCCO>>[NH2:25][CH2:24][CH2:22][O:23][C:2]1[C:7]2[C:8]([CH3:17])=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:18]=[C:19]([CH3:21])[CH:20]=[C:4]2[N:3]=1
Reactant: NCCO
Reactant: CCn1ncc2c1nc(C)c1c(Cl)nc3cc(C)nn3c12
Agent: CN(C)CCCO
Product: CCn1ncc2c1nc(C)c1c(OCCN)nc3cc(C)nn3c12

Procedure:
By substituting the 5-chloro-2,6-dimethyl-8-ethyl-8H pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine obtained in Example 37 in the procedure of Example 21 and substituting ethanolamine for the 3-(dimethylamino)propanol, 5-(2-aminoethoxy)-2,6-dimethyl-8-ethyl-8H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine is obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].CN[C:24]([C:26]1[C:27]([CH3:32])=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25]>CS(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]3[NH:7][C:24](=[O:25])[C:26]4[C:27]([CH:32]=3)=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CNC(=O)c1ccccc1C
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2ccc(N3CCOCC3)cc2)cc2ccccc12
Yield: 41.5 %

Procedure:
4-(4-Morpholinyl)benzonitrile obtained by reacting 4-fluorobenzonitrile (10.89 g) and morpholine (7.84 g) in the presence of potassium carbonate (12.42 g) in dimethyl sulfoxide (45 ml) was reacted with N-methyl-o-toluamide (8.019 g) according to Example 10-1, to give 6.840 g of 3-[4-(4-morpholinyl)phenyl]isoquinolin-1-one.
Reaction SMILES: [C:1]([N:5]1[C:28]2[C:27](=[O:29])[CH2:26][C:10]3([CH2:15][CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12][CH2:11]3)[CH2:9][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC1CC=CCC=1.Cl>C(O)C.[Pd].C(OCC)(=O)C.O1CCOCC1>[C:1]([N:5]1[C:28]2[C:27](=[O:29])[CH2:26][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc2c1C(=O)CC1(CCN(C(=O)OCc3ccccc3)CC1)C2
Agent: [Pd]
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)n1ncc2c1C(=O)CC1(CCNCC1)C2
Temperature: 25 °C
Yield: 110.2 %

Procedure:
A solution of benzyl 1-tert-butyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (46.6 g, 118 mmol) in ethanol (730 mL) was added to 10% palladium on carbon (9.4 g). To this mixture was added 1-methyl-1,4-cyclohexadiene (90 mL, 769 mmol). The reaction was stirred at reflux for 2 hours. The reaction was cooled to room temperature and filtered through Celite®. The filtrate was concentrated in vacuo to give a gray solid. The solid was dissolved in ethyl acetate (150 mL) and to this solution was added 4 M hydrochloric acid in 1,4-dioxane (35 mL). The resulting precipitate was collected by filtration and dried under vacuum to afford the title compound (34 g, 97%) as a white solid. +ESI (M+H) 262.5; 1H NMR (400 MHz, CD3OD, δ): 7.34 (s, 1 H) 3.12-3.25 (m, 4 H) 2.90 (s, 2 H) 2.66 (s, 2 H) 1.67-1.85 (m, 4 H) 1.62 (s, 9 H).
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17].[C:19]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+].C(O)(=O)C>CO>[NH2:1][CH:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:5]2[C:4](=[O:13])[N:3]1[CH2:14][O:15][CH:16]([CH3:18])[CH3:17]
Reactant: O=C1CCCC1
Reactant: CC(C)OCN1C(=O)C2=C(CN)C=NC2=NC1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)OCN1C(=O)C2=C(CNC3CCCC3)C=NC2=NC1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
In 10 ml of dry methanol were dissolved 251 mg of 2-amino-5-aminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one and 252 mg of cyclopentanone and the mixture was allowed to stand under stirring at room temperature for 30 min. The mixture was then cooled to 0° C. and treated with 38 mg of sodium borohydride for 2 hrs. The excess reagent was decomposed with acetic acid, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 218 mg of 2-amino-5-cyclopentylaminomethyl-3-isopropyloxymethylpyrrolo[2,3-d]pyrimidin-4-one. The whole amount of this product was dissolved in 60 ml of 2 N--HCl and, after nitrogen purging, hydrolyzed at 70° C. for 5 hrs. The solvent was then evaporated to dryness under reduced pressure to give 196 mg of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])=[CH:11][C:5]=2[O:4][CH2:3]1.[NH2:20][NH2:21]>C(O)C>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:20][N:21]=3)=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)OCC(=O)N2
Reactant: NN
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)OCC(=O)N2
Yield: 91.6 %

Procedure:
4-(3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyric acid (31 g, 0.12 moles) was dissolved in ethanol (300 ml) and anhydrous hydrazine (4.7 ml, 0.15 moles) was added. The mixture was heated at reflux overnight. White crystals formed after the mixture was cooled. The crystals were collected by filtration and washed well with ethanol. The solid was dried under vacuum giving 28.5 g (93%) of the titled compound, mp 299°-302° C.
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=[O:2].[Cl:8][C:9]1[S:16][C:15]2[CH:14]=[C:13]([C:17]([NH:19][C@H:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]3[NH:29][C:30](N3CCN(C)CC3)=[O:31])=[O:18])[NH:12][C:11]=2[C:10]=1[Cl:39].[CH2:40](Cl)Cl>>[C:30]([N:29]([C@@H:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][C@H:20]1[NH:19][C:17]([C:13]1[NH:12][C:11]2[C:10]([Cl:39])=[C:9]([Cl:8])[S:16][C:15]=2[CH:14]=1)=[O:18])[CH2:3][C:1]([OH:7])=[O:2])(=[O:31])[CH3:40]
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CN1CCN(C(=O)N[C@H]2c3ccccc3C[C@@H]2NC(=O)c2cc3sc(Cl)c(Cl)c3[nH]2)CC1
Product: CC(=O)N(CC(=O)O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
TFA (1 mL) was added to a solution of 1,1-dimethylethyl [acetyl((1R,2R)-2-{[(2,3-dichloro-4H-thieno[3,2-b]pyrrol-5-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)amino]acetate (Method 18, 40 mg, 0.08 mmol) in DCM (5 mL) and the reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure to afford the title compound (35 mg, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH3:16][NH:17][CH3:18]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:17]([CH3:18])[CH3:16]
Reactant: CNC
Reactant: COc1ccc(N)c(CO)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N)c(CN(C)C)c1

Procedure:
2-Amino-N,N-dimethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and dimethylamine analogous to Example 1. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride): 3280 cm-1NH2 ; 3420 cm-1NH2 ; 2780 cm-1N(CH3)2 ; 2830 cm-1OCH3 ; 1600 cm-1C=C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]#[C:12][CH:13]([OH:22])[CH2:14][CH2:15][C:16]2[O:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:6]=[CH:7][CH:8]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:21][C:18]1[CH2:19][CH2:20][C:16](=[O:17])[C:15]=1[CH2:14][CH:13]([OH:22])[C:12]#[C:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(CCC#CC(O)CCc2ccc(C)o2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(CCC#CC(O)CC2=C(C)CCC2=O)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 10.00 g (33.6 mmol) dl-1-(m-methoxyphenyl)-7-(5-methyl-2-furyl)-3-heptyn-5-ol in 20 ml acetic acid, about 10 ml water and 0.40 ml about 20% sulphuric acid was stirred under nitrogen in an oil-bath at 90° C. for about 24 hours. After cooling, the mixture was poured into 200 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue (10.60 g) was dissolved in 500 ml of about 0.1 N ethanolic potassium hydroxide solution and stirred under nitrogen in an oil-bath at about 80° C. for about 1 hour. After cooling, the mixture was poured into 1000 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. Yield: 9.85 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=1)[CH:6]=O.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>CC#N>[CH:17]1([NH:20][CH2:6][C:5]2[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: COCCCOc1cc(C=O)cc(OC)c1
Solvent: CC#N
Product: COCCCOc1cc(CNC2CC2)cc(OC)c1

Procedure:
The title compound is synthesized by reductive amination of 3-Methoxy-5-(3-methoxy-propoxy)-benzaldehyde (2.50 g, 11.1 mmol) with cyclopropylamine (855 mg, 15.0 mmol) analogously to the preparation of Example 152. Yellow oil; MS: 266 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 2.48 min.