Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:7][C:5]([C:8]([O:10]C)=O)([CH2:6]1)[CH2:4][CH2:3][CH2:2]2.[NH3:12].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[N:1]12[CH2:7][C:5]([C:8]([NH2:12])=[O:10])([CH2:6]1)[CH2:4][CH2:3][CH2:2]2
Reactant: N
Reactant: COC(=O)C12CCCN(C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: NC(=O)C12CCCN(C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 1-azabicyclo[3.1.1]hept-5-ylcarboxylate (D4, 1.35 g, 0.0087 mole) was treated with 20M aqueous ammonia solution (25 ml) and the mixture stirred at room temperature for 2 days. The solution was saturated with potassium carbonate and shaken with chloroform (40 ml) The mixture separated into three layers. The chloroform solution contained some product, however the majority was in the middle layer. These two were combined and concentrated in vacuo and the residue then treated with toluene (60 ml) and again concentrated in vacuo to azeotrope out the water. The title compound (D12) remained as a white solid (1.07 g, 88%) m.p. 188°-1920° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:8][CH:9]=1)(=[O:15])[CH3:14]
Reactant: C=CC(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
A solution of acryloyl chloride (29.5 mL, 363 mmol) in CH2Cl2 (50 mL) was added dropwise (30 min) to an ice-cold solution of 4′-aminoacetophenone (49.0 g, 363 mmol) and Et3N (50.6 mL, 363 mmol) in CH2Cl2 (300 mL). The reaction mixture was stirred at 0° for 15 min and then was concentrated under reduced pressure. The residue was dissolved with EtOAc. The solution was washed successively with 10% aqueous HCl, saturated aqueous NaHCO3 and H2O. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the desired N-(4-acetylphenyl)-2-propenamide (52 g, 76% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ8.17 (broad s, 1H), 7.93 (d, J=8.9 Hz, 2H), 7.72 (d, J=8.9 Hz, 2H), 6.47 (dd, J=1.0, 16.9 Hz, 1H), 6.33 (dd, J=10.2, 16.9 Hz, 1H), 5.80 (dd, J=1.0, 10.2 Hz, 1 H), 2.58 (s, 3H); MS (FAB) m/z 190 (MH)+.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:23][CH3:24].[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>CCCCCC.O1CCCC1>[Cl:14][C:15]1[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([CH:31]([C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH2:27][O:26][CH3:25])[OH:32])[CH:18]=[CH:19][CH:20]=1
Reactant: COCOc1ccccc1Cl
Reactant: COCOc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccccc1C(O)c1cccc(Cl)c1OCOC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.6M solution of n-butyl lithium in hexane (140 ml) was placed in a 1 l flask and cooled in an ice bath. To this was added with stirring 34 ml of tetramethylethylenediamine and, after a 10 min reaction period, 34.5 g of 1-chloro-2-methoxymethoxybenzene (dropwise over a 30 min period). A pale orange suspension formed and this was stirred for 4 hours continuing the ice bath cooling. A solution of 34.5 g of 2-methoxymethoxybenzaldehyde in 30 ml of tetrahydrofuran was added with stirring and cooling. The reaction was exothermic. When the addition was complete, the mixture was allowed to warm to room temperature and was then quenched carefully with water. The resulting mixture was poured into a mixture of 1 l of ethyl acetate and 500 ml of aqueous ammonium chloride. The phases were separated and the organic phase was extracted twice with water and once with brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a viscous, pale orange oil. This was purified by filtration chromatography, eluting with mixtures of hexane and dichloromethane starting with pure hexane and ending with pure dichloromethane, to obtain 52.2 g (77 percent of theory) of the title compound as a pale yellow oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH2:17][CH:18]([F:20])[F:19])[CH2:13][C@H:12]1[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:25]>CO.CCOCC>[F:19][CH:18]([F:20])[CH2:17][O:16][C@@H:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:21]([O:23][CH3:25])=[O:22])[CH2:13]1
Reactant: O=C(O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-1-(benzyloxycarbonyl)-4-(2,2-difluoroethoxy)pyrrolidine-2-carboxylic acid (2.0 g, 6.07 mmol) in MeOH and ether (80 ml) (1:1) was added TMS-diazomethane (4.56 mL, 9.11 mmol) (2.0M solution in ether) dropwise at 0° C. The reaction mixture was stirred at RT for 1 h and concentrated. The residue was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[NH2:19])[CH:7]=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][C:10]=2[NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([I:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=S(=O)(Nc1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1)c1ccc(I)cc1
Yield: 61.8 %

Procedure:
Using the method of Example 17.4, 4-(3-chloro-5-pyridyloxy)-3-aminobenzotrifluoride (0.41 g) and 4-iodobenzenesulfonyl chloride (0.30 g) were combined to provide the title compound (0.34 g) as crystals directly from the reaction mixture. mp 192-193° C.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]4[O:11][CH2:1][O:2][C:3]=4[CH:4]=3)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxy-benzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxybenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6](=[O:18])[C:5]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:4]12>C(O)C>[OH:23][CH:3]1[C:4]2[C:5](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6](=[O:18])[N:7]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
Sodium borohydride [1.89 g (50 mmol)] was added to a solution of 2.82 g (10.0 mmol) of 4-(3-phthalimidopropyloxy)pyridine in 150 ml of ethanol. The mixture was stirred at room temperature for 15 minutes. After the solvent was distilled off, brine was added to the residue. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10), and then recrystallized from ethyl acetate to obtain 1.54 g of the desired compound (yield: 54.2%, colroless crystals).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](OC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Solvent: C1CCOC1
Solvent: CSC
Product: CCc1cc(Oc2ccc(CCO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a solution of methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate (0.075 g, 0.20 mmol) in THF (1.3 mL) at 0° C. was added BH3.SMe2 (0.031 g, 0.39 mmol). The mixture was warmed to rt and stirred overnight. After this time, the reaction was quenched with 0.5M HCl, diluted with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, methanol/dichloromethane) to afford the title compound as a white solid (0.052 g, 69%). MW=354.83. 1H NMR (DMSO-do, 500 MHz) δ 8.17-8.10 (m, 2H), 7.59-7.54 (m, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.37-7.32 (m, 2H), 7.22-7.17 (m, 2H), 6.88 (s, 1H), 4.67 (t, J=5.2 Hz, 1H), 3.68-3.62 (m, 2H), 2.79 (q, J=7.3 Hz, 4H), 1.28 (t, J=7.6 Hz, 3H); APCI MS m/z 355 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[NH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[N:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: NN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(C=NN5CCCC5)cc34)cc2Cl)c1
Yield: 81.4 %

Procedure:
In a mixture of 1 mL of tetrahydrofuran and 0.1 mL of water were dissolved 40 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino) 6-formylquinazoline (IV-1) and 13 mg of 1-amino-pyrrolidine hydrochloride, followed by a reaction at room temperature overnight. After the reaction, aqueous saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dehydrated by passing through Presep (registered trademark), and the filtrate was concentrated. The concentrated residue was purified by chromatography (eluting with hexane:ethyl acetate-2:1→1:1) using an amino column to obtain 38 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(pyrrolidin-1-yliminomethyl)quinazoline (IX-1) as a yellow solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[CH2:25][N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10][CH:9]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:7])C>O1CCCC1.O>[C:30]([O:29][C:27]([NH:26][CH:9]1[CH:8]([C:6]([OH:7])=[O:5])[CH2:25][N:12]2[CH2:13][CH2:14][C:15]3[C:20]([CH:11]2[CH2:10]1)=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C1CN2CCc3cc(OC)c(OC)cc3C2CC1NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)CN1CC2
Yield: 99.4 %

Procedure:
Potassium hydroxide pellets (86%, 4.47 g, 68.5 mmol) was added to a suspension of (RS,RS,RS)-2-tert-butoxycarbonylamino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid ethyl ester (7.44 g, 17.1 mmol) in tetrahydrofuran/water 1:1 (140 mL). After heating 5 h at reflux, the mixture was concentrated in vacuo. The residue was taken up in 1M aq. potassium phosphate buffer (pH 6.85) and dichloromethane, and ethanol was added until a clear two-phase mixture was obtained. The organic layer was separated, washed with brine and evaporated to afford the title compound (6.91 g, 99%). Light yellow solid, MS (ISP) 405.3 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([NH2:11])[CH3:10]>ClCCl.CCN(CC)CC>[CH2:9]([NH:11][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:7])[CH3:10]
Reactant: O=C(Cl)c1cccs1
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1cccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Neat thiophene-2-carbonyl chloride (1.46 g, 10 mmol) is added dropwise to a solution of ethylamine (70% wt/water) in Dichloromethane (8 mL) and Et3N at 0° C. Additional ethylamine (2.5 ml, 70% wt/water) is added to the reaction mixture and the reaction is stirred at 0° C. for 2 hrs and the warmed to room temperature for 2 h. The reaction mixture is transferred to a separatory funnel and the organic layer is washed sequentially with aqueous 1N HCl solution, water and saturated aqueous NaHCO3 solution. The organic phase is collected, dried over Na2SO4, filtered and concentrated to give the title compound (1.4 g, 90%).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])=[O:8])=[O:4].O>CO.[Pd]>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CNC(=O)CN
Reaction time: 7 h
Yield: 96.3 %

Procedure:
1.3 g (2.89 mmol) of Z-Gly-Gly-Gly-β-Ala-OtBu was dissolved in 80 mL of 95:5 methanol:deionized water in a 250 mL parr shaker flask to which was added 0.12 g of 10% palladium on carbon. The flask was shaken under a hydrogen atmosphere (42 PSI) for 7 hours. The mixture was vacuum filtered through celite filter aid and the filtrate was concentrated by rotary evaporation under vacuum to give 0.88 g (96%) of the title compound. 1H NMR (d6-DMSO) 8.12 (t, J=1.6 Hz 2H), 8.08 (t, J=1.6 Hz, 1H), 3.75 (s, 2H), 3.64 (d, J=5.9 2H), 3.28 (bs, 2H), 3.24 (q, J=6.0 Hz, 2H), 3.13 (s, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.39 (s, 9H). 13C NMR (d6-DMSO) 173.38, 170.46, 169.18, 168.70, 79.89, 44.65, 41.95, 34.88, 34.78, 27.71. HRMS (M+H+) Calc. 317.1825. found 317.1801
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10](=[O:14])[C:11]#[C:12][CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1>CO>[CH3:1][C:2]1[CH:3]([CH:10]([OH:14])[C:11]#[C:12][CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC#CC(=O)C1C(C)=CCCC1(C)C
Solvent: CO
Product: CC#CC(O)C1C(C)=CCCC1(C)C

Procedure:
The acetylenic carbinol which was obtained as described above under paragraph b) was oxidised as described for its isomer in Example 18, paragraph c. Thus, 1.38 g. of carbinol gave 0.9 g. (66 %) of 2,6,6-trimethyl-1-tetrolyl-2-cyclohexene, b.p. 100°-105°/0.7 Torr. NMR spectrum (CCl4): 0.96 (6 H, d badly resolved), 1.52 (3 H, m), 2.0 (3 H, s), 5.57 (1 H, m), 2.66 (1 H, m) ppm (δ).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8](=[O:34])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]2[C:18](=[O:33])[O:19][C:20]3[CH:21]=[N:22][C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=4)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(OCC)(=O)C>CO>[C:3]([O:7][C:8](=[O:34])[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][CH:17]([CH2:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=3)[N:22]=[CH:21][C:20]=2[OH:19])[CH2:18][OH:33])[CH2:14][CH2:15]1)([CH3:4])([CH3:6])[CH3:5]
Reactant: COc1ccc2ncc3oc(=O)c(C[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)cc3c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2ncc(O)c(CC(CO)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (86 mg, 2.28 mmol, 10.0 eq) is added at 0° C. to a stirred suspension of [trans-4-(6-methoxy-2-oxo-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester (100 mg, 0.23 mmol, 1.0 eq) in methanol (10 mL). After 8 hours stirring at room temperature, the reaction mixture is quenched with ammonium chloride aqueous solution (10 mL), methanol is removed and the resulting residue is extracted with ethyl acetate (3×20 mL) and brine (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 2:1, v/v) to afford {trans-4-[3-hydroxy-2-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (60 mg, 59% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].CO[Na].[NH4+:12].[Cl-]>CO>[CH3:1][C:2]1[O:6][CH:5]=[N:4][C:3]=1[C:7]([NH2:12])=[NH:8]
Reactant: Cc1ocnc1C#N
Reactant: [NH4+]
Agent: CO[Na]
Agent: [Cl-]
Solvent: CO
Product: Cc1ocnc1C(=N)N
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 5-methyloxazole-4-carbonitrile AA (0.76 g, 7.0 mmol) in anhydrous MeOH (30 mL) was added MeONa (0.57 g, 10 mmol), after stirred at 35° C. under nitrogen for 3 h, NH4Cl (0.75 g, 14 mmol) was added, refluxed for 2 h. The solvent was removed and the residue was purified by flash chromatography (Biotage, 40 g silica gel, MeOH in DCM 5%˜35%) to afford brown solid AB (587 mg, 67%). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 9.11-9.19 (m, 3H), 8.60 (s, 1H), 2.59 (s, 3H). MS: calc'd (MH+) 126, measured (MH+) 126.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([C:31]3[N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)[CH2:25][C:26](OCC)=[O:27])=[CH:20][CH:19]=2)=[N:10]1)[CH3:8].O>C1COCC1>[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([C:31]3[N:35]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:34]4[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=4[N:32]=3)[CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=2)=[N:10]1)[CH3:8]
Reactant: CCOC(=O)CC(c1ccc(-c2nn(CC)c3cccnc23)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(-c2ccc(C(CCO)c3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
LiAlH4 (11.99 mg) was added to a solution of ethyl 3-[4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenyl)-3-(1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-benzo[d]imidazol-2-yl)propanoate (90 mg) in THF (10 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere for 1 h. The mixture was poured into water at room temperature and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (80 mg).
Reaction SMILES: Cl.NO.C([N:6](C(C)C)C(C)C)C.C(O)C.[F:16][C:17]([F:50])([F:49])[C:18]1[CH:19]=[C:20]([CH:46]=[CH:47][CH:48]=1)[C:21]([NH:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37]C(=O)OCC)=S)=[N:32][CH:33]=1)=[O:22]>CO>[NH2:37][C:35]1[N:34]=[C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:46]=[CH:47][CH:48]=[C:18]([C:17]([F:16])([F:49])[F:50])[CH:19]=4)[CH:45]=[CH:44][CH:43]=3)=[CH:33][N:32]2[N:6]=1
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Temperature: 60 °C
Yield: 122.2 %

Procedure:
To a solution of hydroxylamine hydrochloride (400 mg, 5.76 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.20 mL, 6.88 mmol) in methanol (8.0 mL)/ethanol (8.0 mL) was added ethyl ({[5-(3-{[3-(trifluoromethyl)benzoyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (480 mg, 0.95 mmol) obtained above, and the mixture was stirred with heating at 60° C. for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and fractions containing the object product was concentrated under reduced pressure to give the title compound (0.48 g, quantitative) as a pale-yellow powder.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([O:19][C@@H:16]2[CH2:17][CH2:18][C@H:13]([C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:14][CH2:15]2)=[CH:25][CH:26]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: O=C([C@H]1CC[C@H](O)CC1)N1CCN(C2CCC2)CC1
Product: O=C([C@H]1CC[C@@H](Oc2ccc(Cl)nc2)CC1)N1CCN(C2CCC2)CC1

Procedure:
According to the procedure described for example 1, the title compound had been synthesized from trans-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone and 2-chloro-5-hydroxypyridine. MS (m/e): 378.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[C:10]([CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[C:10]([CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3cccnc32)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3cccnc32)c1
Yield: 82 %

Procedure:
1-(3-Aminophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (100 mg, 0.28 mmol; prepared in Synthetic Example 7) was heated in acetic anhydride (0.5 ml) and pyridine (0.5 ml) at 100° C. for 20 min, concentrated, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The extract was treated according to conventional techniques. Recrystallization from DMF yielded 1-(3-acetylaminophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (91.3 mg, 82%; mp 200–202° C./DMF).