Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[Cu][C:16]#[N:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([C:16]#[N:17])=[O:13]
Reactant: O=C(Cl)CCCc1ccc(Cl)cc1Cl
Reactant: N#C[Cu]
Product: N#CC(=O)CCCc1ccc(Cl)cc1Cl

Procedure:
By the method of Example 1, Step C, 7.54 g (0.030 mole) of 4-(2,4-dichlorophenyl)butanoic acid chloride and 2.69 g (0.030 mole) of copper(I) cyanide are reacted, yielding 4-(2,4-dichlorophenyl)-butanoyl cyanide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:16][C@H:15]3[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]3)[C:9]([CH3:18])([CH3:17])[C:8]=2[CH:19]=1.O.O.O.[C:23]([O-])(=[O:25])[CH3:24].[Na+].C(OC(=O)C)(=O)C>>[C:23]([N:14]1[C@@H:15]2[C@@H:10]([C:9]([CH3:17])([CH3:18])[C:8]3[CH:19]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=3[CH2:16]2)[CH2:11][CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN[C@H]1C2
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)[C@H]1CCCN(C(C)=O)[C@H]1C2

Procedure:
A mixture of 0.56 g. of cis-1,2,3,4,4a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline hydrochloride, 0.27 g. of sodium acetate trihydrate, and 7 ml. of acetic anhydride was stirred and heated on a steam bath for three hours. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was partitioned between water and diethyl ether. The ether layer was washed with 1N-hydrochloric acid and with saturated aqueous sodium bicarbonate solution. After drying the ethereal solution, filtering, and removing the solvent by evaporation under reduced pressure, there was obtained 0.52 g. of a syrup which crystallized from hexane to yield cis-1-acetyl-1,2,3,4,4 a,5,10,10a-octahydro-7-methoxy-5,5-dimethylbenzo[g]quinoline, m.p. 81°-85°C; ir (CHCl3), 1630 cm.-1 (C=O); nmr (CDCl3), 80 (s,3), 78 (s,3).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: NC(CO)CO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 24.67 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with 2-aminopropane-1,3-diol (38.4 mg, 0.421 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)nicotinamide (26 mg, 0.052 mmol, 24.67% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:36][CH:33]2[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]2)[N:13]=1
Reactant: NC1CCNCC1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC3CCNCC3)nc2n1-c1ccccc1Cl

Procedure:
The product of Example 47, and piperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.21 (m, 2H), 1.84 (m, 2H), 2.38 (m, 2H), 3.01 (m, 2H), 3.30 (m, 1H), 5.36 (s, 1H), 6.40 (d, 1H, J=9.8 Hz), 7.20-7.62 (m, 9H). LC MS (m/e)=466 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:8]2([CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([O:17][CH:18]([O:27][CH2:28][CH3:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:28]([O:27][CH:18]([O:17][CH2:15][CH3:16])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]2[CH2:10][CH2:9][C:8]3([CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:14][CH2:13]3)[CH2:12]2)=[CH:21][CH:20]=1)[CH3:29]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CC(C)CN1CCC2(CCNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CN2CCC3(CCN(CC(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
To a 10% acetic acid-dimethylformamide (10 mL) solution of 8-isobutyl-2,8-diazaspiro[4.5]decane (600 mg) and 4-(diethoxymethyl)benzaldehyde (661 mg), sodium triacetoxyborohydride (1.30 g) was added. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was extracted twice with dichloromethane (20 mL). The combined organic layer was washed with saturated sodium chloride solution (20 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol:28% aqueous ammonia=1:0:0→100:5:1→100:10:2) to obtain the title compound (730 mg) having the following physical properties.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>C(#N)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:14][CH2:13]3)[CH2:11]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Reactant: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
A mixture of 1-[1-(diphenylmethyl)azetidin-3-yl]piperazine (250 mg, 0.81 mmol), K2CO3 (146 mg, 1.1 mmol), propionyl chloride (98 mg, 1.1 mmol) and acetonitrile (6 mL) was stirred at RT for 16 h. The mixture was filtered through a phase separator column and the solvent was removed by evaporation. The residue was dissolved in methylene chloride and the solution washed with aqueous NaHCO3. The organic phase was separated by using a phase separator column and then the solvent was removed by evaporation. There was obtained 216 mg (73%) of 1-[1-(diphenylmethyl)azetidin-3-yl]-4-propionylpiperazine as an oil. 1H NMR (500 MHz, CDCl3): 1.1-1.2 (t, 3H), 2.2-2.4 (m, 6H), 2.9 (t, 2H), 3.0 (m, 1H), 3.4-3.5 (m, 4H), 3.6 (b, 2H), 4.4 (s, 1H), 7.2 (m, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 364 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(C)c1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of 2,3-dimethylphenol (1.0 g, 8.19 mmol), ethyl bromoacetate (1.0 mL, 9.0 mmol) and cesium carbonate (2.67 g, 8.19 mmol) in DMF (10 mL) was stirred at 80° C. for 16 h. After this time, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried and concentrated in vacuo to afford the title compound (1.7 g, 100% yield). LCMS, [M+Na]+=231.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([CH:40]=[CH:41][C:42](O)=[O:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[C:22]([CH:40]=[CH:41][CH2:42][OH:43])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C=CCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-carboxyvinyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in tetrahydrofuran (4 ml), then thereto are added ethyl chloroformate (0.04 ml) and triethylamine (0.06 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is filtered, then thereto is added sodium borohydride (58 mg), and the mixture is stirred for 1 hour and 30 minutes under ice-cooling. 1N-Hydrochloric acid is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine successively, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(3-hydroxypropenyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (155 mg). MS (m/z): 640 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[C:24]([CH2:25]O)=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=[N:21]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[N:20]1[C:24]([CH2:25][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=2)=[C:23]([CH:27]([CH3:29])[CH3:28])[CH:22]=[N:21]1
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: CC(=O)c1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a 0° C. suspension of 4′-Hydroxy-2′-methylacetophenone (716 mg, 4.77 mmol), [2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol (1.36 g, 4.77 mmol), tri-n-butylphosphine (1.78 mL, 7.15 mmol) in toluene (20 mL) is added ADDP (1.80 g, 7.15 mmol). The reaction is warmed to room temperature and is stirred overnight. The reaction is concentrated under reduced pressure and the residue is chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (857 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.42-7.38 (m, 2H), 7.32-7.27 (m, 1H), 6.64-6.58 (m, 2H), 4.85 (s, 2H), 2.99 (sept, 1H, J=7.0 Hz), 2.50 (s, 3H), 2.49 (s, 3H), 1.30 (d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[C:18]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2N)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(C#C[Si](C)(C)C)c2N)CC1
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 4-(5-amino-6-chloropyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1 g, 3.19 mmol) and TMS-acetylene (1.5 g, 15 mmol) in TEA (10 mL) and THF (30 mL) were added PdCl2(PPh3)2 (0.33 g, 0.47 mmol) and CuI (0.1 g, 0.53 mmol) under N2. The mixture was heated to 80° C. for 20 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford the product 4-(5-Amino-6-trimethylsilanylethynyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.3 g, 25%). 1H NMR (CDCl3, 400 Hz) δ 8.00 (s, 1H), 3.74 (s, 2H), 3.28-3.25 (m, 4H), 3.02-2.99 (m, 4H), 1.20 (s, 9H), 0.00 (s, 9H). MS (ESI+) [M+H]+ 376.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([O:26]COCC[Si](C)(C)C)[C:23]4[C:18](=[C:19]([N:37]5[CH2:43][CH2:42][CH2:41][N:40]([CH3:44])[CH2:39][CH2:38]5)[CH:20]=[C:21]([O:35][CH3:36])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[NH:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:35][CH3:36])=[CH:20][C:19]=4[N:37]3[CH2:43][CH2:42][CH2:41][N:40]([CH3:44])[CH2:39][CH2:38]3)=[O:15])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(N2CCCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N2CCCN(C)CC2)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
A solution of 6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 27d) (0.989 g, 1.59 mmol) in 20 mL methanol was poured into 300 mL 0.05 N hydrochloric acid. The clear dark yellow solution became cloudy within 5 minutes. The mixture was stirred at room temperature for 45 minutes and then adjusted to pH 7 with 10% sodium hydroxide. The resulting yellow precipitate was isolated by filtration, washed with water, and dried under high vacuum to afford the desired product as a yellow solid (0.629 g, 80%). 1H NMR (300 MHz, DMSO, d6) δ 9.97 (bs, 1 H,C(O)NH), 7.67 (d, 2 H, Jo=8.8 Hz, ArH2′& H6′), 7.47 (bs, 1 H, ArH5), 7.00 (s, 1 H, C═CH), 6.99 (d, 2 H, Jo=8.8 Hz, ArH3′& H5′), 6.71 (bs, 1 H, ArH7), 3.85 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.6 Hz, OCH2CH2N), 3.70 (bs, 2 H, ArNCH2CH2CH2NCH3), 3.55 (bs, 2 H, ArNCH2CH2NCH3), 3.09 (t, 4 H, J=4.6 Hz, OCH2CH2N), 2.95 (bs, 2 H, ArNCH2CH2NCH3), 2.73 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.36 (s, 3 H, NCH3), 2.07 (bs, 2 H ArNCH2CH2CH2NCH3); Mass Spec.: calc. for [C27H33N5O4+H]+ Theor. m/z=492; Obs.=492. Analysis for C27H33N5O4.1.0 eqHCl. 0.3 eqH2O: Calculated C, 60.79; H, 6.54; N, 13.13. Found C, 60.82; H, 6.53; N, 13.17.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.[CH2:24]([N:26]([CH2:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1)[C:27]([NH:29][CH3:30])=[O:28])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:33]2[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:39])[F:40])=[CH:37][C:32]=2[CH2:31][N:26]([CH2:24][CH3:25])[C:27]([NH:29][CH3:30])=[O:28])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NC
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
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: [K+]
Solvent: COCCOC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)NC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(3-Trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester (0.063 g, 0.18 mmol), 1-ethyl-3-methyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea (0.070 g, 0.18 mmol, potassium carbonate (0.062 g, 0.45 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.02 mmol) were combined in 2:1 DME:H2O (3 mL) and degassed with N2 for 10 minutes. The reaction was then stirred at 90° C. for 2 hours, until no starting material was seen by analytical LCMS. The mixture was cooled to room temperature and used directly in the hydrolysis step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].II.[O:15]=[C:16]([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>O1CCCC1.O>[OH:15][C:16]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CCCC#N)c1cccc(C(F)(F)F)c1
Temperature: 35 °C
Yield: 49 %

Procedure:
A mixture of 7.0 mL (0.05 mole) of 3-trifluoromethylphenyl bromide, 1.2 grams (0.05 mole) of magnesium and a crystal of iodine in about 70 mL of tetrahydrofuran was warmed to 35° C. to initiate the formation of the Grignard reagent. Upon formation of the Grignard reagent, the reaction mixture was cooled to ambient temperature and, with stirring, a solution of 5.8 mL (0.05 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. The reaction mixture temperature increased to about 35° C., at which time the rate of addition was slowed to keep the reaction mixture temperature at about 35°-40° C. The complete addition required about 15 minutes. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for 2 hours. After this time, the reaction mixture was poured into 200 mL of water and was acidified with aqueous 2N hydrochloric acid. The mixture was then extracted with two 150 mL portions of diethyl ether. 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. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.3 grams of 5-hydroxy-5-(3-trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C@@H:7]1([NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH2:13].I[C:16]1[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=1>[Cu]I>[CH3:23][C:18]1[CH:17]=[C:16]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[NH2:14])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C)cc(N[C@@H]2CCCC[C@H]2N)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 40.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (40 mg, 0.210 mmol), K2CO3 (850 mg, 6.15 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (240 μL, 2.00 mmol) and 5-iodo-m-xylene (900 μL, 6.24 mmol) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 100° C. for 23 h. The resulting purple-blue suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 40:1; 15 mL fractions). Fractions 9-13 provided 178 mg (41% yield) of the product as a tan solid. 1H NMR (400 MHz, CDCl3): δ 6.39 (s, 1H), 6.34 (s, 2H), 3.36 (br s, 1H), 3.03−2.92 (m, 1H), 2.56−2.46 (m, 1H), 2.25 (s, 6H), 2.20−2.10 (m, 1H), 2.08−1.95 (m, 1H), 1.83−1.70 (m, 2H), 1.55−1.20 (m, 5H), 1.10−1.00 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=O)[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:19]([CH2:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][C@@H:8]([NH2:7])[CH2:17][CH2:16]3)[CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CN(CC2CCOCC2)C(=O)c2ccc3c(c2)CC[C@H](NC(=O)OC(C)(C)C)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc3c(c2)CC[C@H](N)C3)CC2CCOCC2)cc1
Reaction time: 1 h

Procedure:
A mixture of {(S)-6-[(4-methoxybenzyl)(tetrahydropyran-4-ylmethyl)carbamoyl]-1,2,3,4-tetrahydronaphthalen-2-yl}carbamic acid tert-butyl ester (9.90 g) and dichloromethane (30 ml) was admixed cautiously with trifluoroacetic acid (2.2 g). After one hour, the reaction mixture was basified with saturated potassium carbonate solution. The organic phase was removed, dried over sodium sulfate and concentrated. The crude product was taken up in THF (300 ml) and treated according to method H with lithium aluminum hydride (reaction time 4 hours). The product was thus obtained with the molecular weight of 394.56 (C25H34N2O2); MS
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].[C:23]1(O)C=C[CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9]([O:11][C:12]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:13]=4)=[N:14][C:5]4[N:1]([N:2]=[CH:7][N:6]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Solvent: CCO
Product: c1ccc(Oc2nc3ncnn3c3c2cnc2c3cnn2Cc2ccco2)cc1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid,ethyl ester in Example 1 (a), 8-furfuryl-4H-pyrazolo[4',3'-5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1 (b) and then as in Example 4, substituting phenol for the ethanol to obtain 8-furfuryl- 5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine.