Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+]>O1CCCC1.CO.[Zn]>[NH2:10][C:9]1[C:2]([CH3:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1c(C#N)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(N)cccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a mixture of 2-methyl-3-nitrobenzonitrile (5.50 g, 33.9 mmol) and ammonium chloride (25.4 g, 475 mmol) in tetrahydrofuran (100 mL) and methanol (100 mL) at 0° C. was added zinc dust (31.1 g, 475 mmol) in portions. The mixture was stirred at room temperature for 2 hr. The insoluble material was removed by suction filtration through CELITE®, and the filtrate was concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with CH2Cl2 (4×100 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (4.19 g, 31.7 mmol, 93% yield) as a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:20][CH2:19][CH2:18][O:17]2)=[CH:12][N:11]=1>[Zn].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ni+2].O1CCCC1>[CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:17][CH2:18][CH2:19][O:20]2)=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2OCCO2)cn1
Reactant: BrCc1ccccc1
Agent: [Ni+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: c1ccc(Cc2ccc(C3OCCO3)cn2)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a suspension of zinc (5.0 g, 77 mmol, highly reactive Rieke metal, 100 mL tetrahydrofuran suspension) and tetrahydrofuran (300 mL) was added dropwise benzyl bromide (7.9 mL, 66 mmol) at 0° C., which was stirred for 4 hours at the same temperature. To this suspension were added bis(triphenylphosphine)nickel (II) chloride (5.8 g, 8.8 mmol) and 2-bromo-5-[1,3]dioxolan-2-yl-pyridine (11 g, 49 mmol) described in Manufacturing Example 210-1-2, which was stirred for another 2 hours at room temperature. The reaction solution was partitioned into ethyl acetate and an ammonium chloride aqueous solution. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1) to obtain the title compound (7.3 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][N:39]=1)[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([NH:20][C:21]2[N:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[N:24]=[C:23]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1)=[O:6].CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55](Cl)=[O:56]>C1COCC1>[C:33]([C:23]1[CH:22]=[C:21]([NH:20][C:18](=[O:19])[NH:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:5]([C:4]3[CH:37]=[CH:38][N:39]=[C:2]([NH:1][C:55](=[O:56])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])[CH:3]=3)=[O:6])=[CH:8][CH:9]=2)[N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[N:24]=1)([CH3:34])([CH3:35])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C(=O)c3ccnc(N)c3)c3ccccc23)cc1
Reactant: COCCOCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCC(=O)Nc1cc(C(=O)c2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C

Procedure:
To a solution of 1-(4-(2-aminoisonicotinoyl)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea (38.0 mg, 0.073 mmol) and DIPEA (64 μL, 0.37 mmol) in dry THF (4.0 mL) under N2 at 0° C. was added 2-(2-methoxyethoxy)acetyl chloride (45.0 mg, 0.29 mmol). The reaction mixture was maintained at 0° C. for 30 min and was then warmed to RT for 1.5 hr. The reaction was quenched by the addition of a solution of NH3 (1% in MeOH, 3.0 mL) and after a further 45 min at RT was evaporated in vacuo. The residue was purified by SCX capture and release followed by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-60%, gradient elution) to afford the title compound, Example 22, as a yellow solid (21 mg, 44%); Rt 2.67 min (Method 2); m/z 635 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.29 (9H, s), 2.39 (3H, s), 3.29 (3H, s), 3.50 (2H, m), 3.66 (2H, m), 4.14 (2H, s), 6.45 (1H, s), 7.35-7.37 (3H, overlapping m), 7.46 (2H, d), 7.67-7.73 (3H, overlapping m), 8.20 (2H, m), 8.37 (1H, s), 8.49 (1H, m), 8.54 (1H, d), 9.03 (1H, s), 9.47 (1H, s), 10.24 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])[NH2:5].[N:13]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>Cl.O.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:13])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(N)cc1F
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)cc1F
Temperature: 65 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a stirred suspension of 3-fluoro-4-(methylsulfonyl)aniline (8.1 g, 42.9 mmol) in 20% aqueous HCl (27 mL) was added dropwise a solution of sodium nitrite (3 g, 43.5 mmol) in water (20 mL) at 0° C. After stirring for 1 hour, the resulting suspension was added to a solution of sodium sulfite (13.5 g, 110 mmol) in water (60 mL) and 20% aqueous NaOH (3 mL) at 0-5° C. Then the mixture was heated at 60-70° C. for 2 hours, and conc. HCl (3.5 mL) was added. The resulting mixture was heated for further 5 hours at 60° C. After cooling down to room temperature, the mixture was made basic by Na2CO3. The whole was extracted with THF (150 mL×3), the combined organic layer washed with brine (100 mL), dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized from EtOH to give 3-fluoro-4-(methylsulfonyl)phenylhydrazine (5 g, 57% yield).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:29][O:28][C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[N:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:27]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Oc2cnc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2

Procedure:
A solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyrimidine-2-carboxylic acid tert-butyl ester (171b) (83 mg, 0.21 mmol) in 2 mL CH2Cl2 and 1 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][C:15](C)=[CH:16]C(C)=CC(OC)=O.[O:26]=[O+][O-]>[Zn].C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[C:7](=[O:8])[O:6][CH:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:25])[CH2:14][C:15](=[O:26])[CH3:16]
Reactant: COCC1C(=O)OC1CCCCC(C)CC(C)=CC(C)=CC(=O)OC
Reactant: O=[O+][O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COCC1C(=O)OC1CCCCC(C)CC(C)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 400 mg (1.135 mmole) of methyl 11-(3-methoxymethyl-4-oxo-2-oxetanyl)3,5,7-trimethyl-2,4-undecadienoate in 10 ml of CHCl2 at -78° C., was bubbled ozone for 8 minutes. The resulting mixture was stirred for 30 minutes at -78° C. then at room temperature for another 30 minutes. Acetic acid and zinc dust were added. After stirring for 1 hour at room temperature, the solution was filtered and the filtrate was concentrated to dryness. The product was purified by flash column chromatography to give 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone as a colorless oil. ##STR20##
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O>C(O)C>[CH3:1][NH:2][N:3]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:5]=1[Cl:4]
Reactant: CNN
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: CCO
Product: CNN=Cc1ccc(Cl)cc1Cl
Reaction time: 48 h

Procedure:
263 g (5.7 mol) of methylhydrazine were treated with a solution of 200 g (1.14 mol) of 2,4-dichlorobenzaldehyde in 1.2 l of ethanol. After the mixture had been stirred for 48 hours, the small amount of solids present was filtered off and the filtrate was then concentrated. Yield: quantitative.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[O:8][N:7]=1)=[O:5])C.[CH2:21]([Mg]Br)[CH3:22].Cl>O1CCCC1>[CH2:21]([C:4]([C:6]1[N:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[O:8][N:7]=1)=[O:5])[CH3:22]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)c1noc(COc2ccc(Cl)cc2Cl)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1noc(COc2ccc(Cl)cc2Cl)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
0.95 g of 3-ethoxycarbonyl-5-[(2,4-dichlorophenoxy)methyl]-1,2,4-oxadiazole was added to 30 ml of tetrahydrofuran. The mixture was cooled to -78° C., and then 3 ml of ethylmagnesium bromide (2M solution) was added dropwise. After the mixture was stirred at -78° C. for 1 hour, it was poured into cold aqueous 5% HCl solution. After the resulted product was extracted with ether and concentrated, it was purified by column chromatography(hexane:ethylacetate=4:1) to obtain 0.75 g of the desired product(yield: 83.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:33][NH2:34])(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:34][NH:33][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:16])=[C:5]2[OH:19]
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Cl)ccc2n(C)c1=O

Procedure:
Reagents: Comp 37 (0.36 mmols, 0.10 g); dodecanoyl hydrazine (0.39 mmols, 0.08 g). Yield: 0.143 g (90%), white solid, m.p.=156.5° C.-157.5° C.
Reaction SMILES: [CH2:1]([C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Ca+2].[Cl-].Cl.[CH2:31](C(Cl)(CCCCCCCC)CCCCCCCC)CCCCCCC.C[Al](C)C>C(Cl)Cl>[CH2:1]([C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC(O)(CCCCCCCC)CCCCCCCC
Reactant: CCCCCCCCC(Cl)(CCCCCCCC)CCCCCCCC
Agent: C[Al](C)C
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCC(C)(CCCCCCCC)CCCCCCCC
Temperature: 0 °C

Procedure:
This compound may be prepared in the following manner. Three moles of 1-bromooctane are slowly added to 3 moles of magnesium turnings in 0.6 liters of anhydrous ethyl ether (nitrogen atmosphere). One mole of diethyl carbonate in 0.151 anhydrous ethyl ether is slowly added to the mixture. The mixture is stirred for one hour at 30° C., then the mixture is slowly poured into 1.8 liters of a cold 10% HCl solution. The organic layer is dried with magnesium sulfate and the ethyl ether is evaporated off to give tri-n-octylcarbinol. One mole of tri-n-octylcarbinol is added to a mixture of 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas is slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride is evaporated off. One mole of tri-n-octylmethylchloride is added to 0.75 liters of methylene chloride and the solution is blanketed with nitrogen and is cooled to 0° C. 0.33 moles of trimethylaluminum is then added and the mixture is allowed to warm to room temperature. The mixture is slowly quenched with 50 ml of water followed by washing with 1 liter of a 10% HCl solution. The organic layer is dried with magnesium sulfate and the solvent is evaporated to give tri-n-octylmethylmethane.
Reaction SMILES: [NH:1]([C:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][C:10]([O:12]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:15]([C:8]1[NH:1][C:2]2[C:3]([C:10](=[O:12])[CH:9]=1)=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=CC(=O)OCC)Nc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCCCCCc1cc(=O)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 50 %

Procedure:
The crude product of ethyl 3-anilino-2-decenoate was mixed with diphenyl ether (50 ml) and heated under reflux for 30 minutes. The solution was cooled to room temperature and then diluted with petroleum ether (b.p. 60-80° C.; 200 ml). The mixture was stirred and the petroleum ether decanted off. The product was chromatographed on a silica column using 3% MeOH/CH2Cl2 as the mobile phase. 2-Heptyl-4(1H)-quinolone was obtained as a crystalline solid in 50% yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]12[O:3][C:4]([CH3:8])([CH:14]3[C:10](=[O:9])[N:11]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:25])([F:27])[F:26])[CH:17]=4)[C:12](=[O:15])[CH:13]31)[C:5]([CH3:7])=[N:6]2
Reactant: N#Cc1ccc(N2C(=O)C=CC2=O)cc1C(F)(F)F
Reactant: Cc1nc(C)c(C)o1
Solvent: Cc1ccccc1
Product: CC1=NC2(C)OC1(C)C1C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C12
Temperature: 75 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
2,4,5-Trimethyl oxazole (0.48 mL, 4.14 mmol) was dissolved in toluene (2.0 mL) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-trifluoromethylbenzonitrile (1.00 g, 3.76 mmol) was added. The reaction mixture was stirred at 75° C. under nitrogen for 2.5 hrs. The solution was cooled to room temperature and the resulting precipitate was filtered and rinsed with toluene to give 0.51 g (35%) of compound 211 as a light grey solid. NMR analysis revelaed that compound 211 was one isomer (exo/endo) however the identity of the isomer could not be determined by NMR analysis. HPLC: 100% at 2.85 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 378.42 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:24]=[C:23]3[C:18]([C:19]([NH2:25])=[N:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[C:10](=[O:26])[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:25][C:19]1[C:18]2[C:23](=[CH:24][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:26])=[CH:16][CH:17]=2)[N:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 4-(4-aminoquinazoline-7-ylmethyl)-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.92 g, 5.4 mmol) in EtOAc (200 mL) at 0° C. is saturated with HCl gas. The solution is stirred at 0° C. for 4 hours. After this time, the solution is concentrated. The title compound is obtained as a white solid (1.79 g, 5.4 mmol). 1H NMR (d6-DMSO, 300 MHz) δ9.9 (bs, 3H), 9.7 (bs, 2H), 8.8 (s, 1H), 8.46 (d, 1H), 7.72 (s, 1H), 7.61 (d, 1H), 4.78 (s, 2H), 3.83 (s, 2H), 3.4 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18](=O)[CH2:19][CH2:20][O:21]4)=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:27][OH:28]>>[CH3:1][C:2]1([CH3:25])[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:23]=[C:22]4[C:17](/[C:18](=[N:27]/[OH:28])/[CH2:19][CH2:20][O:21]4)=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1
Reactant: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)OCCC4=O)c2)O1
Reactant: NO
Agent: Cl
Product: CC1(C)OCC(C)(c2csc(Sc3ccc4c(c3)OCC/C4=N\O)c2)O1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 68, 7-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]chroman-4-one was reacted with hydroxylamine hydrochloride to give (E)-7-[4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-ylthio]chroman-4-one oxime in 65% yield as a gum.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]3)=[CH:42][N:41]=2)[C:26]2[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]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2].O.C(OCC)(=O)C.[CH3:64][N:65](C)C=O>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.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:64]#[N:65])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:47][CH2:48][N:49]([C:52](=[O:54])[CH3:53])[CH2:50][CH2:51]3)=[CH:42][N:41]=2)[C:26]2[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
(2R,4S)-4-{[5-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis-(trifluoromethyl)benzyl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg), a catalytic amount of tetrakis(triphenylphosphine)palladium, zinc cyanide (37 mg) are dissolved in N,N-dimethylformamide (2 ml), and the mixture is stirred at 100° C. for 6 hours under nitrogen flow. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate. The mixture is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=3:7→0:1) to give (2R,4S)-4-{[5-(4-acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (149 mg). MS (m/z): 705 [M+H]+.
Reaction SMILES: ClC1C=CC(C2C3C=CC(=O)NC=3C3C(C)=NOC=3CN=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]3[CH:45]=[C:44]([O:46]C)[N:43]=[CH:42][C:33]=3[C:34]3[C:40]([CH3:41])=[N:39][O:38][C:35]=3[CH2:36][N:37]=2)=[CH:27][CH:26]=1.ClC1N=CC2C3C(C)=NOC=3CN=C(C3C=CC(Cl)=CC=3)C=2C=1.ClC1C=CC(C2C3C(OC)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1.ClC1C=CC(C2C3C=CC(OC)=NC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]3[C:33](=[CH:42][NH:43][C:44](=[O:46])[CH:45]=3)[C:34]3[C:40]([CH3:41])=[N:39][O:38][C:35]=3[CH2:36][N:37]=2)=[CH:27][CH:26]=1
Reactant: COc1cc2c(cn1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1
Agent: COc1ccc2c(n1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1
Agent: COc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Agent: Cc1noc2c1-c1[nH]c(=O)ccc1C(c1ccc(Cl)cc1)=NC2
Product: Cc1noc2c1-c1c[nH]c(=O)cc1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 5-(4-chlorophenyl)-10-methyl-1H-isoxazolo[5,4-c]pyrido[2,3-e]azepin-2(7H)-one was followed, except that 6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepine (prepared from 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepine in a similar fashion to 6-(4-chlorophenyl)-7-methoxy-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepine) was used as starting material instead of 5-(4-chlorophenyl)-2-methoxy-10-methyl-7H-isoxazolo[5,4-c]pyrido[2,3-e]azepine. LC/MS m/z 326 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (br. s, 1H), 7.92 (br. s, 1H), 7.48 (s, 4H), 6.25 (br. s, 1H), 4.78 (br. s, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH2:18]([O:20][C:21](=[O:33])[CH:22]([OH:32])[CH:23]([NH3+:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:19]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:31][CH:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:22]([OH:32])[C:21]([O:20][CH2:18][CH3:19])=[O:33])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction was carried out in analogy to reaction step 20.1 by reacting (R)-1-benzyl-5-oxopyrrolidine-2-carboxylic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+=425.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=O)[N:14]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1.B.O1CCCC1.Cl.[OH-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[CH2:15][N:14]([CH:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(CCC)N1C(=O)C(C)Oc2c(-c3ccc(C)cc3C)cccc21
Agent: B
Agent: Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(CCC)N1CC(C)Oc2c(-c3ccc(C)cc3C)cccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a solution of 8-(2,4-dimethylphenyl)-2-methyl-4-(1-propylbutyl)-2H-1,4-benzoxazin-3(4H)-one (50 mg, 0.14 mmol) was added dropwise to borane-tetrahydrofuran complex (1M solution in tetrahydrofuran, 1.37 ml, 1.4 mmol) in tetrahydrofuran (2 ml) with ice-cooling. The mixture was refluxed for 24 h and then decomposed at room temperature by dropwise addition of 6N hydrochloric acid (2 ml). The mixture was stirred at 50° C. for 30 min. The acidic solution was made alkaline with excess ammonium hydroxide, and the basic mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 1% ethyl acetate/n-hexane to afford 15 mg (31%) of the title compound.