Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.C(OC([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([O:18][C:19]2[CH:38]=[CH:37][C:22]3[C:23]4[N:27]([CH2:28][CH2:29][O:30][C:21]=3[CH:20]=2)[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:24]=4)[CH2:13]1)=O)(C)(C)C>CO>[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([O:18][C:19]2[CH:38]=[CH:37][C:22]3[C:23]4[N:27]([CH2:28][CH2:29][O:30][C:21]=3[CH:20]=2)[CH:26]=[C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[N:24]=4)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3c(c2)OCCn2cc(-c4ccccn4)nc2-3)C1
Solvent: CC(=O)Cl
Solvent: CO
Product: c1ccc(-c2cn3c(n2)-c2ccc(OC4CCCNC4)cc2OCC3)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To an ice-cooled solution of MeOH (4 mL) was added dropwise acetyl chloride (1.5 mL) and the mixture was stirred for 30 min at RT. A solution of impure 3-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy)piperidine-1-carboxylic acid tertbutyl ester coming from the previous step in MeOH (1 mL) was then added and the reaction mixture was stirred for 2 h at RT. A white solid was filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 35-85% 0.1% NH4OH in acetonitrile/water, RT 10.6 min) affording 8-(Piperidin-3-yloxy)-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (13 mg, 6% over two steps).
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:5][C@@:6]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].[CH3:35]I.[H-].[Na+]>C1COCC1>[CH3:34][C:2]([CH3:1])([CH2:5][C@@:6]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH3:35])[CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: CI
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (202 mg, 0.444 mmol) and MeI (110 μL, 4 equiv) in dry THF (5 mL) was cooled to 0° C. NaH (60% in mineral oil, 36 mg, 2 equiv) was added. After 10 min, the mixture was warmed to rt slowly and stirred for 3 h. LC-MS showed about 50% conversion. The mixture was heated for 1 h at 60° C. LC-MS found the reaction completed. After cooling to rt, the mixture was cooled to 0° C. and quenched with satd aq NH4Cl (3 mL). The mixture was then diluted with CH2Cl2 (20 mL), washed with 1% aq HCl (5 mL) and brine (4 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by prep HPLC to afford 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (177.4 mg, 85% yield) product as a light brown oil.
Reaction SMILES: C[O:2][C:3]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]([O:24]C)=[C:18]([CH3:26])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:26][C:18]1[C:19](=[O:24])[C:20]([CH3:23])=[C:21]([CH3:22])[C:3](=[O:2])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][C:16](=[O:27])[CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOc1ccc(Cc2c(C)c(OC)c(C)c(C)c2OC)cc1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Yield: 68 %

Procedure:
5-(2,5-Dimethoxy-3,4,6-trimethylbenzyl)-2-etoxybenzoic acid (1.25 g, 2.56 mmol) was dissolved in a mixed solution of acetonitrile (30 ml) and water (10 ml) and after adding thereto CAN (3.50 g, 6.39 mmol), the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) and then recrystallized from ether to obtain the titled compound (0.800 g, 1.74 mmol, 68%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].Cl>O>[CH2:13]([O:12][C:10]([NH:1][CH:2]([CH:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: Cl
Solvent: O
Product: CC(O)C(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 18 h
Yield: 102.8 %

Procedure:
To a solution of D-threonine (50.7 g, 0.426 mol) in water (800 ml) at about 0° C. was added benzyl chloroformate (66 ml, 0.462 mol) dropwise over about 15 minutes. The reaction was allowed to warm to about 23° C. and was stirred at that temperature for about 18 hours. The reaction was cooled with ice and acidified with concentrated hydrochloric acid, extracted with ether (3 times) and the organic layers were concentrated to give 110.9 g of 2-benzyloxycarbonylamino-3-hydroxy-butyric acid as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](Cl)=[N:33]1)=O)(C)(C)C.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:34]4[C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[NH:32][N:33]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: CC(C)(C)OC(=O)n1nc(Cl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4n[nH]c5ccccc45)cc3CC[C@@H]12
Yield: 41.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-(t-butoxycarbonyl)-3-chloroindazole (116 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 60 mg (16%) of the title compound as an oil. FDMS: m/e=377.
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:18][C:19]=2[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1>CC(O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:18][C:19]=2[CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)C(O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Sodium borohydride(95 mg) was added to a tetrahydrofuran(60 ml)-2-propanol(30 ml) solution of ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(2.93 g) at 0° C. After stirring for 30 minutes, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-hydroxyacetate(2.20 g, 75%). This was recrystallized from acetone-ethyl acetate to give colorless prisms. mp 197-198° C. (degradation)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:13]#[C:14][C:15]2[O:19][C:18]([C:20](=[O:24])[CH2:21][C:22]#[N:23])=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>>[NH2:23][CH2:22][CH2:21][CH:20]([C:18]1[O:19][C:15]([C:14]#[C:13][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:16][CH:17]=1)[OH:24]
Reactant: N#CCC(=O)c1ccc(C#CC2CCCCC2)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCC(O)c1ccc(C#CC2CCCCC2)o1

Procedure:
LiAlH4 reduction of 3-(5-(cyclohexylethynyl)furan-2-yl)-3-oxopropanenitrile following the method used in Example 1 gave after flash chromatography purification (2%-20% 7N NH3/MeOH—CH2Cl2 gradient) followed by treatment with activated charcoal Example 23 as a light yellow oil. Yield (0.14 g, 26%); 1H NMR (400 MHz, CD3OD) δ 6.39 (d, J=3.4 Hz, 1H), 6.24 (d, J=3.9 Hz, 1H), 4.68 (t, J=6.8 Hz, 1H), 2.69-2.79 (m, 2H), 2.56-2.64 (m, 1H), 1.90-1.98 (m, 2H), 1.81-1.90 (m, 2H), 1.68-1.80 (m, 2H), 1.28-1.68 (m, 6H); RP-HPLC tR=9.95 min; ESI-MS m/z 230.2 [M−H2O+H]+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17](OCC(Cl)(Cl)Cl)=O)[N:14]([CH:25]([N+:36]#[C-])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>CN(C)C=O.C(OCC)(=O)C.[Zn]>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:13](=[O:38])[N:14]2[CH:15]1[S:16][CH:17]=[N:36][CH:25]2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#[N+]C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N=CSC12
Reaction time: 0.17 h
Yield: 48.1 %

Procedure:
To a solution of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-isocyanoacetate (2.20 g.) in N,N-dimethylformamide (15 ml.) was added zinc powder (3.30 mg.) at 0° C., and the mixture was stirred at the same temperature for 10 minutes. Thereto was added dropwise acetic acid (2.0 ml.) over a period of 3 minutes and the mixture was stirred at 0° C. for 25 minutes. The reaction mixture was diluted with ethyl acetate (50 ml.) and filtered through a pad of Celite. To the filtrate was added ethyl acetate (50 ml.) and washed with a mixture of 5 to 6% aqueous solution of sodium bicarbonate (60 ml.) and a saturated aqueous solution of sodium chloride (30 ml.), a dilute aqueous solution of sodium chloride (30 ml.×2), a saturated aqueous solution of sodium chloride (30 ml.), water (50 ml.) and a saturated aqueous solution of sodium chloride successively. Drying and removal of the solvent left an amorphous solid (1.51 g.). Chromatography on silica gel (15 g.) with a mixed solvent of methylene chloride and ethyl acetate (5:1 by volume) as an eluent and crystallization from diethyl ether gave benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate (750 mg.), mp 141.5°-143.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[N:19][N:18]([CH3:21])[C:17]=3[CH:22]=2)[NH:9][NH:10][CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C.[CH:27](=N)[NH2:28].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:9]2[CH:27]=[N:28][CH:11]=[N:10]2)[C:13]2[CH:14]=[CH:15][C:16]3[N:20]=[N:19][N:18]([CH3:21])[C:17]=3[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc2ccc(C(NNC=O)c3ccc(Cl)cc3)cc21
Reactant: N=CN
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cn1nnc2ccc(C(c3ccc(Cl)cc3)n3cncn3)cc21
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 5 g of intermediate 7-a, 8.2 g of methanimidamide monoacetate in 32 ml of methanol was refluxed for 3 days. To the warm reaction mixture there were added 32 ml of water and the resulting mixture was stirred for two hours. The precipitate was filtered off and washed with 2-propanol. The precipitate was dried in vacuo, yielding 3.45 g (67%) of (+)-6-[(4-chlorophenyl)-(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole (comp. 1-e); enantiomeric excess: 97.4%.
Reaction SMILES: [Cl:1][C:2]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:28][CH2:29][CH2:30][CH2:31][N:5]([CH2:4][C:3]1[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([F:25])([F:26])[F:27])[C:2]=1[Cl:1])[CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(CN(CCCBr)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.3 %

Procedure:
A solution of compound (2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amine (2.5 g, 6.5 mmol) and 1,3-dibromo propane (3.2 ml, 32 mmol) in acetonitrile (300 ml) was treated with solid potassium carbonate (1.8 g, 13 mmol). The reaction was heated to reflux and stirred for 48 h. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (EtOAc:Hexane/20:80) to give the title compound as an oil (2.2 g, 67%). MS m/e 510.6 (M+H)+.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([S:33][CH3:34])=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([S:33][CH3:34])=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylaniline (3.2 g, 26.6 mmol) and phosphorus oxychloride (32.6 g, 213 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4(4aH)-one (7.6 g, 26.6 mmol) in 1,2-dichloroethane (20 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 1 hr. Reaction mixture was poured into ice, neutralized by solid sodium carbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and light brown oil residue was directly gone to next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[C:18]([O-])(=[O:20])C.[Na+].C(O)(=O)C.C=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH2:18][OH:20])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccc(C2CCc3nccn32)cc1F
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C2CCc3ncc(CO)n32)cc1F

Procedure:
A solution of product from Step H (3.79 g, 16.7 mmol), sodium acetate (2.44 g, 29.7 mmol), acetic acid (1.82 mL, 31.9 mmol), and formaldehyde (37% in water, 15.1 mL) was heated to reflux for 96 hours. The reaction was slowly neutralized by the addition of sat. aq. NAHCO3. The aqueous layer was extracted with methylene chloride (5×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (1→10% MeOH/CHCl3) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:13][C:14]([OH:16])=O)[C:3]=12.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: C1COCCN1
Reactant: Cc1cc(C)c2c(OCC(=O)O)nsc2n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c2c(OCC(=O)N3CCOCC3)nsc2n1
Yield: 82 %

Procedure:
Alternatively, the coupling reaction of acid 26 with morpholine in the presence of EDCI, DMAP and DIEA, by a procedure similar to that for compound 21 (YMU1), gave compound 27 in 82% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=O)=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[N:24]1[S:25][N:26]=[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[N:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH:36]=O)[CH:30]=[CH:29][C:28]=12.O>C1COCC1>[N:24]1[S:25][N:26]=[C:27]2[CH:32]=[C:31]([N:33]3[C:34]4[C:35](=[CH:38][CH:39]=[CH:40][N:41]=4)[CH:36]=[C:10]([CH2:9][CH2:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[C:11]3=[O:13])[CH:30]=[CH:29][C:28]=12
Reactant: O=Cc1cccnc1Nc1ccc2nsnc2c1
Reactant: CCOC(=O)CCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(CCCc2ccncc2)cc2cccnc2n1-c1ccc2nsnc2c1
Yield: 43 %

Procedure:
Ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq., prepared in Synthetic Example 2) was dissolved in dry THF. To the solution was added LDA (2M solution, 1.5 eq.) at −78° C. or below in a dry ice-methanol bath under nitrogen atmosphere while stirring and the mixture was stirred for 1 hour. Next, to the reaction mixture was added dropwise a solution of 2-(2,1,3-benzothiadiazol-5-ylamino)-nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1a)) in THF and the resultant mixture was stirred for 2 hours at −78° C. and then continued to stir for 24 hours until it reached room temperature. The reaction mixture was treated with water, and extracted with methylene chloride. The extract was dried, and evaporated. To the residue was added ethyl acetate to form crystals. Thus, 1-(2,1,3-benzothiadiazol-5-yl) -3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one was obtained. The product was purified through flash column chromatography and recrystallization (yield: 43%, mp 193.5–195.5° C./DMF).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]([C:9]1[O:10][C:11]2[C:16]([C:17](=[O:26])[C:18]=1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[C:13]([Cl:27])[CH:12]=2)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>C(Cl)Cl.CCOCC>[CH2:19]([C:18]1[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([Cl:27])=[CH:14][CH:15]=2)[O:10][C:9]=1[CH:5]([NH:4][CH2:3][CH2:2][NH:1][C:41](=[O:42])[C:38]1[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=1)[CH:6]([CH3:7])[CH3:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCNC(c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Yield: 50.6 %

Procedure:
To a cooled (0° C.) solution of 2-[1-(2-amino-ethylamino)-2-methyl-propyl]-3-benzyl-7-chloro-chromen-4-one (4.1 g, 11 mmol) and triethylamine (2.2 mL, 17 mmol) in methylene chloride (100 mL) was added a solution of p-toluoyl chloride (1.7 g, 11 mmol) in methylene chloride (20 mL). The reaction was maintained at 0° C. for 2 hours, at which time it was diluted with ether (250 mL). The resultant solution was washed with 1 N hydrogen chloride (2×200 mL), saturated sodium bicarbonate (200 mL) and brine (150 mL), dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (0→60% ethyl acetate/hexanes) to give 2.8 g (50%) of the title compound. MS (ES+) m/e 503 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:34])[N:18]([CH3:33])[C:19]2[CH:20]=[N:21][C:22]([O:25][C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:23][CH:24]=2)=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:33][N:18]([C:19]1[CH:20]=[N:21][C:22]([O:25][C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:23][CH:24]=1)[C:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][CH:9]=1)=[O:34]
Reactant: Cc1ncccc1Oc1ccc(N(C)C(=O)c2cn(C(=O)OC(C)(C)C)c3ccccc23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncccc1Oc1ccc(N(C)C(=O)c2c[nH]c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
The tert-butyl-3-(methyl(6-(2-methylpyridine-3-yloxy)pyridine-3-yl)carbamoyl)-1H-indole-1-carboxylate (40 mg, 0.087 mmol) was added to a mixed solution of dichloromethane (1 ml) and TFA (1 ml), and the mixture was stirred at room temperature for 1 hour. Subsequently, the product was filtered, washed, and dried to yield a target compound as a white solid (28 mg, 90%)
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[C:19]#[N:20])[CH:12]=[C:11]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:10]=1.C(N(CC)C(C)C)(C)C.[O:39]1[CH2:42][C:41](=O)[CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl>[CH3:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[C:19]#[N:20])[CH:12]=[C:11]([CH:24]2[CH2:29][CH2:28][N:27]([CH:41]3[CH2:42][O:39][CH2:40]3)[CH2:26][CH2:25]2)[CH:10]=1
Reactant: Cc1cc(C2CCNCC2)cc(Nc2cc(C#N)ccn2)n1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CCN(C3COC3)CC2)cc(Nc2cc(C#N)ccn2)n1
Reaction time: 17 h
Yield: 32.8 %

Procedure:
To a suspension of 2-((6-methyl-4-(piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile mono-TFA salt (33.8 mg, 0.0830 mmol) in anhydrous THF (0.8 mL) was added N,N-diisopropylethylamine (24 μL, 0.17 mmol) followed by 3-oxetanone (8.0 μL, 0.12 mmol) and the mixture was stirred for 15 min before the introduction of sodium triacetoxyborohydride (55 mg, 0.25 mmol). After stirring for a further 17 hr, the mixture was diluted with CH2Cl2 and washed with sat. aq. NaHCO3 and the organics were dried over MgSO4 and concentrated to dryness. The residue thus obtained was purified by RPLC to afford 2-((6-methyl-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile as a colorless solid (9.5 mg, 34%); 1H NMR (400 MHz, DMSO) δ 9.99 (br s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.36 (s, 1H), 7.21 (d, J=5.1 Hz, 1H), 6.75 (s, 1H), 4.54 (dd, J=6.5, 6.5 Hz, 2H), 4.45 (dd, J=6.5, 6.5 Hz, 2H), 3.42 (m, 1H), 2.80 (m, 2H), 2.44 (m, 1H), 2.40 (s, 3H), 1.86 (m, 2H), 1.76 (m, 2H), 1.63 (m, 2H); ESI-LRMS m/z [M+1]+=350.
Reaction SMILES: [Mg].[Br-].C(OCC)C.[CH2:8](Br)[CH:9]=[CH2:10].[CH3:12][C:13]1([CH3:23])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([CH3:21])([CH3:20])[C:14]1=[O:22]>>[CH2:10]([C:14]1([OH:22])[C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][CH2:18][CH2:19][C:13]1([CH3:23])[CH3:12])[CH:9]=[CH2:8]
Reactant: C=CCBr
Reactant: CC1(C)CCCCC(C)(C)C1=O
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: C=CCC1(O)C(C)(C)CCCCC1(C)C
Yield: 74.5 %

Procedure:
Magnesium (5.37 g, 0.221 moles) was added to 500 ml four-necked flask equipped with a mechanical stirrer, a dropping funnel, a thermometer, a reflux condenser and a nitrogen gas inlet tube, into which nitrogen gas was passed to remove moisture from the flask. Thereafter, a small amount of a mixed solution of ally bromide (1.5 g, 0.0124 moles)/dried diethyl ether (7.5 ml) was dropped while stirring, followed by dropping a mixed solution of allyl bromide (21.29 g, 0.176 moles)/2,2,7,7-tetramethylcycloheptanone (24.68 g, 0.147 moles)/dried diethyl ether (75 ml) in 2 hours while cooling to 15° C. or below on an iced water bath. The resulting mixture was stirred for 1 hour while keeping at 15° C. or below. Thereafter, the reaction mixture was treated in the same manner as in Example 1, thereby obtaining 23.03 g (yield 74.5%) of the captioned compound. This compound was a colorless transparent liquid having a woody, green, earthy and patchuli oil-like odor.