Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:6]=1.[CH3:23][Mg]Br.Cl>C1COCC1.CC(OC)(C)C>[F:20][C:17]([F:18])([F:19])[CH2:16][O:15][C:7]1[CH:6]=[C:5]([C:4](=[O:21])[CH3:23])[CH:10]=[CH:9][C:8]=1[C:11]([F:12])([F:13])[F:14]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzamide from step 7 (10.467 g, 32 mmol) in THF (100 mL) at −5° C. was added methylmagnesium bromide (3 M in Et2O, 21.1 mL, 64 mmol). The mixture was stirred at 0° C. for 15 min, then warmed up to 23° C., stirring was continued for further 1.5 h at 23° C. Cooled to 0° C., 1 N HCl (150 mL) was added drop wise, stirring was continued at 23° C. for 15 min, the mixture was diluted with TBME, the phases were separated, the organic layer was washed with water and brine, dried over MgSO4. Removal of the solvent in vacuum left a yellow solid (9.021 g, 100%), which was used without further purification. MS (EI) 286.1 [M].
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([O:11][C@@:12]1([CH2:44][CH3:45])[C:17]2[CH:18]=[C:19]3[N:27]([C:28](=[O:29])[C:16]=2[CH2:15][O:14][C:13]1=[O:43])[CH2:26][C:25]1[C:24]([CH2:30][CH2:31][Si:32]([CH3:38])([CH3:37])[CH2:33][CH2:34][CH2:35][NH3+:36])=[C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]2=[N:21][C:20]3=1)(=[O:10])[CH3:9].[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:38][Si:32]([CH3:37])([CH2:33][CH2:34][CH2:35][NH:36][C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])[CH2:31][CH2:30][C:24]1[C:25]2[CH2:26][N:27]3[C:19](=[CH:18][C:17]4[C@@:12]([O:11][C:8](=[O:10])[CH3:9])([CH2:44][CH3:45])[C:13](=[O:43])[O:14][CH2:15][C:16]=4[C:28]3=[O:29])[C:20]=2[N:21]=[C:22]2[CH:42]=[CH:41][CH:40]=[CH:39][C:23]=12
Reactant: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCC[NH3+]
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])C(F)(F)F
Product: CC[C@@]1(OC(C)=O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCNC(=O)Nc1ccccc1

Procedure:
The required product was prepared according to Procedure E, above, using Compound 21 and phenyl isocyanate. The required product was obtained in 50% yield.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+]>C(OC(C)(C)C)(=O)C>[C:3]([O:26][C@@H:20]([C:4]1[C:3]([CH3:27])=[C:2]([F:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:12][S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:27])([CH3:4])[CH3:2]
Reactant: CCOC(=O)[C@@H](O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 5 h
Yield: 162.2 %

Procedure:
A solution of (S)-ethyl 2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (1.02 g, 2.49 mmol) in tert-butyl acetate (20 mL) was treated with 70% HClO4 (20 μL) at 23° C.). After 5 h, the reaction was added slowly over 5 min to saturated NaHCO3 (40 mL). The resulting system was extracted with DCM (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane→ethyl acetate/hexane 1:4) giving the desired product (942 mg, 81% yield). 1H NMR (400 MHz, CDCl3) δ 8.11-8.02 (m, 2H), 7.65-7.60 (m, 2H), 5.72 (s, 1H), 4.25-4.13 (m, 2H), 2.45 (d, JHF=3.2 Hz, 3H), 1.21 (s, 9H), 1.18 (t, J=7.0 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−123.1 (ap s, 1F), −73.3 (s, 3F).
Reaction SMILES: CO[CH:3]([O:27][CH3:28])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1.C[Si]([C:33]#[N:34])(C)C.B(F)(F)F.CCOCC>ClCCl>[CH3:28][O:27][CH:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][C:14]3[N:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:17][C:18]=3[CH3:19])=[CH:10][C:9]=2[CH:26]=1)[C:33]#[N:34]
Reactant: C[Si](C)(C)C#N
Reactant: COC(Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(C#N)Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Yield: 85.9 %

Procedure:
To a solution of 5-(2,2-dimethoxyethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methyl]benzofuran (0.75 g, 2.0 mmol) in dichloromethane (15 ml) were added trimethylsilyl cyanide (0.80 ml, 6.0 mmol) and boron trifluoride etherate (50 μl, 0.5 mmol). After 1 hour the solution was diluted with dichloromethane, washed with 5% sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated. The product was purified by flash-chromatography (hexanes/ethyl acetate, 2:1) and isolated as a solid (0.64 g, mp 107°-109° C.).
Reaction SMILES: [OH-:1].[K+].OO.[CH2:5]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[N:13]1)=S)[CH2:6][CH2:7][CH3:8].Cl>CO>[CH2:5]([NH:9][C:10]([N:12]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=2)=[N:13]1)=[O:1])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCNC(=S)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: CCCCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
Potassium hydroxide (0.42 g, 7.5 mmol) and 30% hydrogen peroxide (2.7 ml) were added to a solution of N-butyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carbothioamide (0.98 g, 2.5 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid was added to the reaction mixture up to a pH of 1, and the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15 ml×3), and the organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10→1/1), to give a colorless viscous substance of N-butyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.17 g, yield: 18.1%). 1H-NMR (CDCl3, TMS, ppm): δ 0.94 (t, J=7.3 Hz, 3H), 1.30-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.65 (s, 3H), 3.35 (dt, J=6.3 and 6.3 Hz, 2H), 6.04 (s, 1H), 6.90-7.20 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 8.35 (m, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[N:4][C:5]([C:8]2[N:12]=[CH:11][N:10](C3CCCCO3)[N:9]=2)=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].ClCCl.Br[C:53]1[N:58]=[C:57]2[N:59]([CH2:64][CH3:65])[C:60](=[O:63])[CH2:61][NH:62][C:56]2=[N:55][CH:54]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH2:64]([N:59]1[C:57]2=[N:58][C:53]([C:2]3[C:3]([CH3:19])=[N:4][C:5]([C:8]4[NH:12][CH:11]=[N:10][N:9]=4)=[CH:6][CH:7]=3)=[CH:54][N:55]=[C:56]2[NH:62][CH2:61][C:60]1=[O:63])[CH3:65]
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Reactant: CCN1C(=O)CNc2ncc(Br)nc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCN1C(=O)CNc2ncc(-c3ccc(-c4nnc[nH]4)nc3C)nc21
Temperature: 90 °C
Yield: 57 %

Procedure:
A mixture of 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (1 equiv), bis(pinacolato)diboron (1.05 equiv), potassium acetate (2 equiv), potassium carbonate (3 equiv), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.1 equiv) in anhydrous dioxane (300 mL) was degassed and heated at 90° C. for 2 h. The mixture was cooled to <40° C. and 7-bromo-1-ethyl-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), water and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.05 equiv) were added. The mixture was degassed and heated at 65-70° C. under nitrogen for 1 h. The mixture was cooled to <40° C., diluted with water and ethyl acetate. Standard ethyl acetate/water work up followed by flash column chromatography (0-5% methanol in dichloromethane) and recrystallization from ethanol gave the title compound in 57% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.99 (s, 2H), 7.93 (s, 1H), 7.72 (s, 1H), 4.22 (s, 2H), 4.05 (q, J=6.77 Hz, 2H), 2.71 (s, 3H), 1.18 (t, J=7.03 Hz, 3H); MS (ESI) m/z 337.6 [M+1]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]2)=[CH:25][CH:24]=1.CON(C)[C:43]([CH:45]1[CH2:47][CH2:46]1)=[O:44]>C1COCC1.CCOC(C)=O>[CH:45]1([C:43]([C:30]2[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:32][N:28]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:39][CH:38]=3)[N:29]=2)=[O:44])[CH2:47][CH2:46]1
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Reactant: CON(C)C(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 9.7 %

Procedure:
According to Scheme 16: Butyl lithium 2.5 M (9.9 mmol, 4 mL) was added to a solution of diisopropylamine (9.9 mmol, 1.4 mL) in THF (20 mL) at −78° C. and the reaction mixture was stirred at −78° C. for 5 minutes and then at room temperature. To the resulting LDA solution was added at −78° C. a solution of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (7.61 mmol, 1.98 g) in THF (30 mL) and the reaction mixture was stirred for 15 minutes at −78° C. Then N-methoxy-N-methylcyclopropanecarboxamide (9.14 mmol, 1.18 g) in THF (10 mL) was added and the reaction mixture was stirred at room temperature. The reaction mixture was diluted with AcOEt and washed with a saturated aqueous solution of NH4Cl. The combined organic phases were dried over MgSO4, were filtered and solvents were evaporated. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10) as eluent to yield ethyl 3-(cyclopropanecarbonyl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (0.74 mmol, 244 mg, 9%).
Reaction SMILES: ICI.[CH2:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH3:18]C(OC(OC(OC(C)(C)C)=O)=O)(C)C.CCN(C(C)C)C(C)C>C1COCC1.[Zn].Cl[Cu].C(OCC)C.C(COC)OC>[CH2:18]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Temperature: 15 °C
Reaction time: 20 h
Yield: 61.1 %

Procedure:
In a baked-out dry flask under protective gas (argon), a mixture of 9.90 g of zinc dust (151 mmol) and 1.50 g of CuCl (15.15 mmol) in 20 ml of abs. diethyl ether was stirred at 50° C. (bath temperature) for approx. 100 min. The mixture was cooled to 15° C. (bath temperature). 6.1 ml of diiodomethane (75.0 mmol), 7.8 ml of abs. dimethoxyethane and finally 4.27 g of tert-butyl 4-methylenepiperidine-1-carboxylate (21.7 mmol) were successively and rapidly added dropwise. The reaction mixture was heated gradually to 50° C. (bath temperature) and stirred at this temperature for approx. 20 h. After this time, owing to still incomplete conversion, another 20 ml of diethyl ether and 6.1 ml of diiodomethane were added with cooling. The reaction mixture was heated to 50° C. (bath temperature) for a further 8 h. Cooling was followed by dilution with THF and filtration through Celite. The filtrate was admixed with 4.3 g of p-toluenesulfonic acid and a few drops of water, and then concentrated under reduced pressure. The crude product thus obtained was dissolved in 100 ml of THF and admixed with 7.09 g of Boc anhydride (1.5 eq.) and 5.5 ml of DIPEA (1.5 eq.). The mixture was stirred at RT for 48 h and then concentrated under reduced pressure. The residue thus obtained was stirred with approx. 150 ml of diethyl ether. The mixture was filtered with suction and the filter residue was washed thoroughly with diethyl ether. The filtrate thus obtained was concentrated. What remained was an oil which was taken up in 200 ml of dichloromethane and was washed twice with sat. NaHCO3 solution and once with dil. HCl solution (pH=5). The organic phase was dried over MgSO4 and then concentrated under reduced pressure. In this way, 2.8 g of tert-butyl 6-azaspiro[2.5]octane-6-carboxylate were obtained as a light-colored oil. This oil was dissolved in 5 ml of dichloromethane and admixed with a mixture of 10 ml of TFA and 0.5 ml of water. After stirring at RT for 48 h, the reaction solution was concentrated under reduced pressure and codistilled with toluene three times more. In this way, 6-azaspiro[2.5]octane was obtained as a TFA salt in the form of a brown oil which was clean enough for further reactions.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(C)cc(O)n1
Product: CSc1nc(C)cc(Cl)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-Hydroxy-6-methyl-2-(methylthio)pyrimidine (9.20 g, 59 mmol) and phosphorous oxychloride (60 mL) were combined and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resultant aqueous mixture was extracted with ethyl acetate; and the organic layer washed with saturated aqueous sodium bicarbonate followed by a water wash, dried over magnesium sulfate, and dried in vacuo to give 4-chloro-6-methyl-2-(methylthio)pyrimidine (8.27 g, 80%), m.p. 37-38° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:15])([CH2:13][OH:14])[C:10]([OH:12])=[O:11].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>ClCCl>[F:8][C:9]([F:15])([CH2:13][O:14][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])[C:10]([OH:12])=[O:11]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)C(F)(F)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(F)(F)C(=O)O
Reaction time: 8 h

Procedure:
To a mixture of 250 mL dichloromethane with 10.1 g (100 mmol) of triethylamine is added 12.6 g (100 mmol) of 2,2-difluoro-3-hydroxypropanoic acid and the resulting mixture is placed into an ice bath. 10.5 g (100 mmol) of methacryloyl chloride is added slowly into the flask and reaction is kept stirring for overnight. The resulting mixture is then washed with 200 mL of 1% NaHCO3 solution and the solvent is then subsequently removed. The product is then recrystallized from methanol to provide 2,2-difluoro-3-(methacryloyloxy)propanoic acid, in expected good yield, which is used for following synthesis without further purifications.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([C:35]3[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)cn1

Procedure:
Under the same conditions as the method for synthesizing Compound B2-22-1, the title compound was prepared from Compound B1 and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [N:1]1([C:7]2[C:8]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]3=[O:26])=[N:9][C:10]3[C:15]([C:16]=2[N+:17]([O-])=O)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.[Pd]>[NH2:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[C:7]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1c1nc2ccccc2c([N+](=O)[O-])c1N1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1c(N2CCCCC2)c(C2CCCCC2=O)nc2ccccc12

Procedure:
The 3-piperidino-4-nitro-2-(2'-oxocyclohexyl)quinoline (8.5 g, 0.024 mol) was dissolved in tetrahydrofuran (50 ml) and subjected to reduction in the presence of 10g palladium-on-carbon (1.2 g). After completion of the reaction, the palladium-on-carbon catalyst was filtered off and the mother liquor was concentrated. Following purification by chromatography on an alumina column using chloroform as a developing solvent, recrystallization from ethanol was conducted to obtain 4-amino-3-piperidino-2-(2'-oxocyclohexyl)quinoline in an amount of 6.1 g (yield, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH3:10])[C:4](=[O:18])[CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH3:8][C:6]1[N:5]([CH:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH3:10])[C:4](=[O:18])[CH:3]=[C:2]([O:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:7]=1
Reactant: Cc1ccc(C(C)n2c(C)cc(O)cc2=O)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)n(C(C)c3ccc(C)nc3)c(=O)c2)cc1
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A stirred mixture of the product from Step 1 (475 mg, 1.947 mmol) and 4-methylbenzenesulfonyl chloride (371 mg, 1.947 mmol) in anhydrous dichloromethane (16 ml) was treated with anhydrous triethylamine (0.81 ml, 5.839 ml) and stirring was continued at ambient temperature for 18 h. The reaction mixture was diluted with dichloromethane (150 ml), washed with water (100 ml) followed by brine (100 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash silica chromatography eluting with ethyl acetate to give toluene-4-sulfonic acid 6-methyl-1-[1-(6-methyl-pyridin-3-yl)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl ester (609 mg) as a colourless gum which solidified on standing. LC-MS m/z 399 [M+H]+ Rt=2.10 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:58][CH:59]([CH3:61])[CH3:60])[C:7]([F:57])=[C:8]([CH:10]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[N:55]=[C:54]([CH3:56])[O:53][N:52]=3)=[CH:47][CH:46]=2)[C:11]2[N:12]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=[C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18](O)=[O:19])[N:15]=2)[CH:9]=1)[CH3:2].[NH2:62][CH2:63][CH3:64].Cl.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:58][CH:59]([CH3:61])[CH3:60])[C:7]([F:57])=[C:8]([CH:10]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[N:55]=[C:54]([CH3:56])[O:53][N:52]=3)=[CH:47][CH:46]=2)[C:11]2[N:12]([C:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=[C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([NH:62][CH2:63][CH3:64])=[O:19])[N:15]=2)[CH:9]=1)[CH3:2]
Reactant: CCN
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(=O)O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OCC)cc(OC(C)C)c2F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of Intermediate 133.1 (crude, ˜30 mg), NH2Et.HCl (7 mg, 0.13 mmol), HOAt (41 mg, 0.3 mmol), EDCI (58 mg, 0.3 mmol), NaHCO3 (50 mg, 0.6 mmol) in 4:1 CH2Cl2/DMF (2 mL) was stirred at rt for 2 h. The reaction mixture was then partitioned between EtOAc and sat. NaHCO3, the organic layer was then washed by NH4Cl, and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated to afford Intermediate 133.2. The crude material was used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:21][NH:20][C:19](=[O:22])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].[C@@H]1(N)CCCC[C@H]1N>CCOC(C)=O.[Cu]I.O1CCOCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:21][N:20]([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[C:35]#[N:36])[C:19](=[O:22])[CH2:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2CNC(=O)C2)c(OCc2ccccc2)c1
Reactant: N#Cc1cccc(Br)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(=O)N(c3cccc(C#N)c3)C2)c(OCc2ccccc2)c1
Temperature: 110 °C
Yield: 81.2 %

Procedure:
4-(2-Benzyloxy-4-methoxyphenyl)-pyrrolidin-2-one (2.0 g. 6.8 mmol), potassium phosphate (2.56 g, 1.8 eq), and 3-bromobenzonitrile (1.82 g, 1.5 eq) was added to a flask under N2. The mixture was charged with 10 mL DMF and 10 mL dioxane followed by the addition of 1,2-trans-cyclohexanediamine (100 μL) and CuI (180 mg). The mixture was heated at 110° C. for 20 h and cooled down to r.t. Next the mixture was diluted with 150 mL EtOAc, washed with sat. NH4Cl, water, and brine, and then dried. After concentration, the residue was purified on silica gel (EtOAc: Hexane=3:1) to give 2.2 g of the desired product. Yield: 81%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][NH:9][C:8](=[O:13])[C:5]21[CH2:7][CH2:6]2.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH3:3][N:4]1[C:11](=[O:12])[CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](=[O:13])[C:5]21[CH2:7][CH2:6]2
Reactant: CN1C(=O)CNC(=O)C12CC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CN(Cc2ccccc2)C(=O)C12CC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.8 %

Procedure:
Sodium hydride (302 mg, 12.62 mmol) was taken up in DMF (10 mL) and cooled to 0° C. for 30 min. Then a mixture 4-methyl-4,7-diazaspiro[2.5]octane-5,8-dione (1.769 g, 11.47 mmol) in DMF (5 mL) was slowly added over 10 min. This mixture was allowed to stir for 45 min, and then benzyl bromide (4.08 mL, 34.41 mmol) was added, and the reaction was stirred for 45 min further. The mixture was carefully diluted with water (10 mL) and concentrated in vacuo. The resulting crude product was purified via reverse phase HPLC to provide 4-methyl-7-(phenylmethyl)-4,7-diazaspiro[2.5]octane-5,8-dione (1.535 g, 54%). LCMS: (M+H)+: 245.1.