Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenyl)benzoic acid (100 mg, 0.2369 mmol) and piperidine (40 mg, 0.4705 mmol) were dissolved in methylene chloride (20 ml), then 4-dimethylaminopyridine (6 mg, 0.0491 mmol) and WSC-HCl (136 mg, 0.7094 mmol) were added thereto and the mixture was stirred for 6 hours at room temperature. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (58 mg, 0.1186 mmol, 50%).
Reaction SMILES: [OH-:1].[Na+].OO.[CH2:5]([NH:7][C:8]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[C:21]3[N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[N:28]=[CH:27]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])[CH3:6].O>CS(C)=O>[CH2:5]([NH:7][C:8]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[C:21]3[N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[N:28]=[CH:27]2)[CH:13]=[CH:12][C:9]=1[C:10]([NH2:11])=[O:1])[CH3:6]
Reactant: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C(N)=O
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([S:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 177.2 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (1 g, 4.65 mmol) in EtOH (13 ml) was added to a solution of benzylmercaptan (0.65 ml, 5.53 mmol), Na2CO3 (0.64 g, 6.1 mmol) and water (3 ml) and the reaction was heated under reflux for 4 h. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration, washed with n-hexane and dried to give the title compound (2.5 g, 88%). The structure was confirmed by 1H NMR.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.[B:42](OC(C)C)([O:47]C(C)C)[O:43]C(C)C>C1COCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:17]2[CH:16]=[C:15]([B:42]([OH:47])[OH:43])[C:14]([F:13])=[N:19][CH:18]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)nc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 36.1 mL, 90 mmol) was added to a stirred solution of diisopropylamine (12.8 mL, 90 mmol) in tetrahydrofuran (150 mL, 75 mmol) at −40° C. and the slightly yellow solution was stirred at the same temperature for 1 h, and then cooled to −78° C. A solution of tert-butyl 4-((6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (22.22 g, 75 mmol) in THF (100 mL) was cannulated slowly into the LDA solution over 30 min. The brown mixture was stirred at the same temperature for 1.5 h and then a solution of triisopropyl borate (25.9 mL, 113 mmol) in THF (50 mL) was added slowly. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1.0 M NaOH(aq) (50 mL) and stirred for an additional 30 min. The separated aqueous layer was carefully acidified with 5 N aqueous HCl until acidic (pH 4 to about 5) and the resulting cloudy mixture was diluted with EtOAc (150 mL). The separated aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (21.93 g, 64.7 mmol, 86% yield) as a pale yellow solid. LCMS (API-ES) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:5]=1[CH2:21]Br.[SH:24][CH2:25][C@H:26]([NH:33][C:34](=[O:36])[CH3:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([Br:10])=[C:8]([O:11][CH3:12])[CH:7]=[C:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:5]=1[CH2:21][S:24][CH2:25][C@H:26]([NH:33][C:34](=[O:36])[CH3:35])[C:27]1[O:31][N:30]=[C:29]([CH3:32])[N:28]=1
Reactant: COC(=O)c1c(Br)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1CBr
Reactant: CC(=O)N[C@@H](CS)c1nc(C)no1
Product: COC(=O)c1c(Br)c(OC)cc(O[Si](C)(C)C(C)(C)C)c1CSC[C@H](NC(C)=O)c1nc(C)no1

Procedure:
6-Bromo-2-bromomethyl-3-(tert-butyl-dimethylsilanyloxy)-5-methoxy-benzoic acid methyl ester and (R)-N-[2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide were subjected in an analogous manner to the procedure described in Example 6(b) to yield (R)-2-[2-acetylamino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-6-bromo-3-(tert-butyl-dimethyl-silanyloxy)-5-methoxybenzoic acid methyl ester as a pale yellow oil.
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:30])=[C:16]([N:25]([C:27](=[O:29])[CH3:28])[CH3:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C)C=O>[C:10]([NH:13][C:14]1[C:15]([I:30])=[C:16]([N:25]([C:27](=[O:29])[CH3:28])[CH3:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl ethyl carbonate (10.00 g, 66.0 mmol) was added dropwise during 1.5 hour at room temperature to a solution of potassium 5-(N-acetylamino)3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (40.00 g, 60.0 mmol) and sodium iodide (0.89 g, 6.0 mmol) in dry dimethylformamide (200 ml). After stirring at 50° C. for 24 hours the solvent was removed at reduced pressure. The residue was dissolved in chloroform (120 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate, treatment with activated charcoal and filtration, the title compound was crystallised by concentrating the solution at reduced pressure. Yield: (79%). Purity by HPLC: 99%. 1H-NMR (DMSO-d6): delta=1.25 (t, J=7 Hz, CH3); 1.64 (d, J=6 Hz, CH3); 1.67 (s, N(Me)COCH3); 2.05(s, NCOCH3); 2.96 (s, NCH3); 4.21 (q, J=7 Hz, CH2); 6.97 (q, J=6 Hz, CH); 10.10 ppm (s, NH).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1Nc1ccc(OC(F)(F)F)cc1
Yield: 84 %

Procedure:
4,6-Dichloro-5-methylpyrimidine (534.6 mg, 3.3 mmol) and 4-trifluoromethoxy aniline (661 mg, 3.6 mmol) were dissolved in EtOH and DIEA (625 uL, 3.6 mmol) was added and the mixture was refluxed for 4 h. It was then cooled, concentrated and work-up with ethyl acetate. The organic layer was separated and dried (Na2SO4). Concentrated and purified by silica-gel column chromatography (Ethyl acetate/hexane). 800 mg (84% Yield), MS m/z 304.14 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[C:9](=[N:18]\[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])/[N:10]([CH3:17])[CH2:11][C:12]([O:14]CC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(Cl)Cl>[C:22]([O:21][C:19]([NH:18]/[C:9](=[N:8]\[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])/[N:10]([CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:20])([CH3:24])([CH3:25])[CH3:23]
Reactant: CCOC(=O)CN(C)/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CC(=O)O)/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl N—{(E)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}-N-methylglycinate (630 mg, 1.75 mmol) was dissolved in tetrahydrofuran (6.3 mL) at room temperature. To this was added 1.0 M aqueous sodium hydroxide (0.75 mL, 1.75 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum to remove the tetrahydrofuran. The mixture was cooled in an ice bath and acidified with 1 M aqueous sulfuric acid (1.72 mL, 1.75 mmol). The mixture was diluted with methylene chloride, and then the water was removed using anhydrous magnesium sulfate. After filtering, the methylene chloride was removed under vacuum to give the title compound in a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:8][CH2:7][CH2:6]2.[C:18]([S:21][CH2:22][CH:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:20])[CH3:19].O>CC(N(C)C)=O>[C:18]([S:21][CH2:22][CH:23]([CH3:27])[C:24]([N:13]([CH:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH2:14][C:15]([OH:17])=[O:16])=[O:25])(=[O:20])[CH3:19]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COc1ccc2c(c1)CCCC2NCC(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)CCCC2N(CC(=O)O)C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
N-(6-Methoxy-1,2,3,4-tetrahydro-1-naphthyl)glycine (3.0 g) is suspended in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 20 ml of 10% hydrochloric acid and with water, and dried over anhydrous sodium sulfate. Ethyl acetate is distilled off under reduced pressure, 10 ml of ethyl ether is added to the residue, and the mixture is allowed to stand at room temperature. Collection of the resulting crystalline precipitate by filtration gives 1.9 g of N-(3-acetylthio-2-methylpropionyl)-N-(6-methoxy-1,2,3,4-tetrahydro-1-naphthyl)glycine as colorless needles. Melting point: 158°-161° C.
Reaction SMILES: [Na].[C:2]([O:8]CC)(=O)[CH2:3][C:4]([O-:6])=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])[CH:16]=[CH:17][CH:18]=1>CCO>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][N:21]2[C:2](=[O:8])[CH2:3][C:4](=[O:6])[NH:24][C:22]2=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1cccc(CCNC(N)=O)c1
Agent: [Na]
Solvent: CCO
Product: COc1cccc(CCN2C(=O)CC(=O)NC2=O)c1

Procedure:
Sodium (236 mg, 10.2 mmol, 2 eq.) was added to degassed EtOH (18 mL), when sodium dissolved completely, ethyl malonate (1.56 mL, 10.2 mmol, 2 eq.) was added and the reaction was refluxed for 1 h. Intermediate 1 (995 mg, 5.12 mmol, 1 eq.) in EtOH (4 mL) was then added and the reaction was refluxed for 1 day. The desired intermediate 37 1-[2-(3-methoxy-phenyl)-ethyl]-pyrimidine-2,4,6-trione precipitated upon addition of 2N aqueous HCl, it was filtered and washed with H2O and finally dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])O.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:23][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Temperature: 22 °C

Procedure:
A mixture of 2,5-bis(benzyloxy)phenol (0.28 g), 2-bromoacetophenone (0.22 g), potassium hydrogen-carbonate (0.25 g) and 18-Crown-6 (3 mg) in acetonitrile (4.2 ml) was stirred at 22° C. for one week. The mixture was filtered and evaporated to dryness under reduced pressure. The residue was triturated with the mixture of ether (8.2 ml) and water (1.4 ml) at the ice bath temperature. The product was collected by filtration, washed with cold ether and dried under reduced pressure. Yield is 0.14 g. 1H NMR (DMSO-d6) δ: 4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s, 2H), 6.51 (dd, J 8.9, 2.3 Hz, 1H), 6.68 (d, J 2.3 Hz, 1H), 6.94 (d, J 8.9 Hz, 1H), 7.28-8.03 (m, 15H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]C(=O)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:28])[CH3:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91259.9 %

Procedure:
A solution of 5.41 g (0.02 mmol) of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester in ethanol (50 mL) is degassed with nitrogen over 0.5 h and 2.34 g (0.04 mol) of KOH are added, followed by 8.14 g (0.04 mol) of ethyl α-bromoisobutyrate. The reaction is stirred for 18 h at room temperature under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure. The residue is partitioned between DCM (100 mL) and water (100 mL). The organic layer is washed with water (50 mL), brine (250 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and purified by column chromatography (silica, eluent heptanes, 50% ethyl acetate) to afford 6.05 g of 4-(1-ethoxycarbonyl-1-methyl-ethylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. Yield: 87%; ES-MS: m/z 354 [M+Na], 232 [[M+H—C5H9O2]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.25-1.35 (3H, m), 1.46 (9H, s), 1.48-1.53 (2H, m), 1.55 (6H, s), 1.88 (2H, dd, J=13.31, 3.47 Hz), 2.94-3.04 (3H, m), 3.81-3.92 (2H, m), 4.19 (2H, q, J=7.10 Hz)
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].C[O:12][CH:13](OC)[CH2:14][CH2:15][CH2:16][CH:17]=O>CCOC(C)=O.CCCCCC>[N+:1]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH:13]=[O:12])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: O=[N+]([O-])Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCCC=C(c1ccccc1)[N+](=O)[O-]
Yield: 41.1 %

Procedure:
Prepared according to the general procedure B from 1-(nitromethyl)benzene 112d (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (E/Z=6.7/1) (1.44 g, 41% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36](B(O)O)=[C:35]([O:43][CH3:44])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: COc1cc(F)c(F)cc1B(O)O
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic separation. Light brown solid (91%). MS (ESI): m/z=251.099 [M+H]+.
Reaction SMILES: [ClH:1].[CH:2]1([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[C:11]([C:20]([N:22]3[CH2:27][CH:26](C)[NH:25][CH:24]([CH3:29])[CH2:23]3)=[O:21])=[CH:10]2)C[CH2:6][CH2:5][CH2:4][CH2:3]1.I[CH2:31][CH3:32]>>[ClH:1].[CH:2]1([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:18][CH3:19])[C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:24][CH3:29])[C@H:31]([CH3:32])[CH2:23]3)=[O:21])=[CH:10]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cccc2c(C(=O)N3CC(C)NC(C)C3)cn(CC3CCCCC3)c12
Reactant: CCI
Agent: Cl
Product: CCN1CCN(C(=O)c2cn(CC3CCCC3)c3c(OC)cccc23)C[C@H]1C

Procedure:
(R)-1-{[1-(Cyclopentylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-4-ethyl-3-methylpiperazine, hydrochloride salt was prepared using (R)-1-{[1-(cyclopentylmethyl)-7-methoxy-1H-indol-3-yl]carbonyl}-3-methylpiperazine (prepared as detailed in example 12) and iodoethane. 1H NMR (400 MHz, CD3OD) δH 1.24-1.42 (8H, m), 1.51-1.73 (6H, m), 2.43 (1H, heptet, J 7.6), 3.12-3.23 (2H, m), 3.47-3.71 (5H, br m), 3.95 (3H, s), 4.38 (2H, d, J 6.9), 4.51 (2H, br s), 6.77 (1H, d, J 8.2), 7.10 (1H, t, J 7.7), 7.26 (1H, d, J 8.1), 7.60 (1H, s). EIMS; m/z=384.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:12](=[O:14])O[C:10]([CH3:15])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].CO>N1C=CC=CC=1>[CH3:15][C:10]1[N:17]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[C:12](=[O:14])[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 170 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Step 4: Two vials each with a suspension of 5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and 3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) in pyridine (15 mL) were heated at 170° C. for 10 minutes in a microwave oven. The suspension was filtered and washed with pyridine (5 mL). The filtrate was concentrated in vacuo. The resulting mixture was stirred in HCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2 hours. The suspension was filtered and washed with water (30 mL) and ethyl acetate (30 mL) to give a dark brown solid, which was stirred with methanol (50 mL) at room temperature overnight. The suspension was filtered and washed with methanol to give 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a black solid (490 mg, 27% yield). The solid was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2Cl)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1c1ccc(Cl)cc1Cl
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
Methyl 2-(2,4-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.55 g, 3.85 mmol) was dissolved in MeOH (15.79 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.014 mL, 3.85 mmol) in water (1.579 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.236 mL, 3.85 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (19.91 mL, 119.45 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Methyl 2-(2,4-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.870 g, 60.8%) was isolated as a white solid. MS m/z 371 (M+H)+