Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].BrBr.Br[O-].[CH2:7]([O:14][CH2:15][C:16]12[CH2:24][CH:20]3[CH2:21][CH:22]([CH2:23]1)[C:18]([C:25](=[O:27])C)([CH2:19]3)[CH2:17]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(O)=[O:30]>O1CCOCC1.O>[CH2:7]([O:14][CH2:15][C:16]12[CH2:24][CH:20]3[CH2:21][CH:22]([CH2:23]1)[C:18]([C:25]([OH:30])=[O:27])([CH2:19]3)[CH2:17]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: CC(=O)C12CC3CC1CC(COCc1ccccc1)(C3)C2
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C12CC3CC1CC(COCc1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a mixture of NaOH (30.6 g, 765 mmol), H2O (255 mL) and 1,4 dioxane (51 mL) at ice bath temperature was added Br2 (15.2 mL, 285.6 mmol) and stirred for 15 minutes. This hypobromite solution was added dropwise to a stirred solution of 1-{1-[(benzyloxy)methyl]tricyclo[3.3.1.03,7]non-3-yl}ethanone (14.5 g, 51.0 mmol) in 1,4-dioxane (51 mL) at ice bath temperature. The reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was cooled to ice bath temperature and quenched by adding AcOH (46.7 mL, 765 mmol). The reaction mixture was diluted with water, extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-[(benzyloxy)methyl]tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (8.0 g) as white solid in 55% yield. m/z (M−1), 285; 1H NMR (CDCl3) 300 MHz δ 7.40-7.22 (m, 5H), 4.50 (s, 2H), 3.27 (s, 2H), 2.70-2.62 (m, 1H), 3.47-3.38 (m, 1H), 2.16 (s, 2H), 2.12-1.98 (m, 2H), 1.90-1.55 (m, 7H), 1.50 (dd, J=3.0, 11.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][OH:14])[CH2:9]2)=[CH:4]1.Cl[C:16]1[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=[C:18]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])[N:17]=1>CN(C)C=O>[F:30][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:24]=1[C:18]1[N:17]=[C:16]([O:14][CH2:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:5]3[CH:6]=[CH:7][S:3][CH:4]=3)[CH2:9]2)[N:21]([CH3:22])[C:20](=[O:23])[CH:19]=1
Reactant: OC[C@H]1CCN(c2ccsc2)C1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(OC[C@H]2CCN(c3ccsc3)C2)nc(-c2ccncc2F)cc1=O
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a slurry of sodium hydride (60 wt % in mineral oil, 0.04 g, 1.0 mmol) in N,N-dimethylformamide (2 ml) under nitrogen atmosphere was added (S)-[1-(thiophen-3-yl)pyrrolidin-3-yl]methanol (0.13 g, 0.70 mmol) in N,N-dimethylformamide (1 ml) at room temperature. The resulting mixture was stirred for 15 minutes. To the mixture was added 2-chloro-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.14 g, 0.60 mmol) at room temperature. After the mixture was stirred for 3 hours, the reaction was quenched with water and partitioned between water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 0/100) to afford 6-(3-fluoro-pyridin-4-yl)-3-methyl-2-[(3S)-1-thiophen-3-yl-pyrrolidin-3-ylmethoxy]-3H-pyrimidin-4-one (0.045 g, 0.12 mmol, 19%) as a yellow solid.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]=[O:16]>C(O)CCC>[C:1]1([C@H:7]([N:9]([CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[CH2:15][O:16][CH2:6][CH2:1][CH2:2][CH3:3])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: C[C@@H](NC[Si](C)(C)C)c1ccccc1
Solvent: CCCCO
Product: CCCCOCN(C[Si](C)(C)C)[C@H](C)c1ccccc1

Procedure:
The title compound was prepared from (R)-(+)-N-1-phenylethyl-N-trimethylsilylmethylamine by reaction with n-butanol and aqueous formaldehyde following the procedure of Example 2 to give the crude acetal (85% pure) as a colourless oil (34.2 g, 84%). The nmr spectrum was identical to the above (S)-isomer.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15].CCCCCC>CN(C=O)C.O.CCOCC>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:6]=1
Reactant: FC(F)(F)CCCCBr
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)CCCCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a stirred solution of 4-iodo-1H-pyrazole (337 mg, 1.737 mmol) in DMF (10 mL) was added sodium hydride (104 mg, 2.61 mmol). After 30 min, 5-bromo-1,1,1-trifluoropentane (427 mg, 2.085 mmol) was added. The reaction was stirred at rt for 2 h. 3:1 hexane:ether and water were added. The organic layer was washed with H2O, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g silica gel, eluted with 0-60% EtOAc in hexanes) to give the desired product (460 mg, 83%) as clear oil. LCMS Anal. Calc'd for C8H10F3IN2 318.0, found [M+H] 319.0. 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.40 (s, 1H), 4.12 (t, J=6.9 Hz, 2H), 2.00-2.15 (m, 2H), 1.85-1.96 (m, 2H), 1.47-1.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:29][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.C(=O)([O-])[O-:31].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:29][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([NH2:28])=[O:31])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: N#Cc1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Temperature: 0 °C

Procedure:
A solution of 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile 278 in DMSO was treated with potassium carbonate and the resultant yellow suspension cooled to 0° C. The reaction mixture was treated dropwise with hydrogen peroxide (30% wt. in water). The whole was warmed to room temperature and the reaction quenched with sat. NaHSO3. Extraction with ethylacetate and concentration gave a residue that was purified by reverse phase HPLC to give 295 as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:50])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.34 mmol) prepared in Example 5 and Lawesson's Reagent (270 mg, 0.61 mmol) in THF (5 mL) was stirred at room temperature for 1 h, then purified by flash column chromatography to give the title compound as white solid (130 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:20]#[N:21])[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[N:6]([C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[C:13]2[C:14]([C:20]=1[NH2:21])=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:22])[CH3:2]
Reactant: CCOC(=O)CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N)c2cc(Cl)ccc2n1C(=O)C(F)(F)F
Yield: 85.5 %

Procedure:
Under nitrogen, stir and cool to 0° C. a solution [(4-chloro-2-cyanophenyl)-(2,2,2-trifluoro-ethanoyl)amino]-acetic acid ethyl ester (93.34 g, 10 mmol) in tetrahydrofuran (20 mL) and add, dropwise, a 1M solution of potassium tert-butoxide in tetrahydrofuran (12 mL, 12 mmol). Stir the reaction at ambient temperature for 2 h and then partition between aqueous ammonium chloride/ethyl acetate. Separate the organic layer, dry over MgSO4, filter and concentrate to a solid. Triturate the solid with heptane, filter the solid and air dry to obtain 2.86 g (86%) of the title compound: MS 335(M+H), m.p. 249–251° C.
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:7]1)(=O)C.[OH-].[Na+]>Cl>[NH2:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:7]1
Reactant: CC(=O)NCC1CN(Cc2ccc(C(F)(F)F)cc2)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCC1CN(Cc2ccc(C(F)(F)F)cc2)CCO1

Procedure:
A solution of crude 2-(N-acetylaminomethyl)-4-(p-trifluoromethylbenzyl)morpholine (17.06 g) in 10% aqueous hydrochloric acid (200 ml) was heated under reflux for 3 hours. After cooling, the reaction mixture was made basic by the addition of 50% aqueous sodium hydroxide (100 ml) and then extracted with chloroform (100 ml×3). The combined organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure to give crude 2-aminomethyl-4-(p-trifluoromethylbenzyl)morpholine. A total yield of 2 steps=100%. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[N:17][S:18][CH:19]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:18]1[CH:19]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:16]=[N:17]1
Reactant: Brc1cnsc1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cnsc2)C1=O
Yield: 54.4 %

Procedure:
1-(4-Methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 4-bromo-isothiazole (166 mg, 1.016 mmol), 1,4-dioxane (15 mL), copper iodide (16.09 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.254 mmol) and potassium phosphate (540 mg, 2.541 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHl3) afforded 120 mg of the product (54.54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]2[O:15][C:14]([Si](C(C)C)(C(C)C)C(C)C)=[N:13][CH:12]=2)=[C:6]([NH2:8])[CH:7]=1.[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]2=[C:28]([C:35](O)=[O:36])[CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]2[O:15][CH:14]=[N:13][CH:12]=2)=[C:6]([NH:8][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:31]=[CH:32][CH:33]=[N:34][C:29]=23)=[O:36])[CH:7]=1
Reactant: CC(C)[Si](c1ncc(COc2ccc(Cl)cc2N)o1)(C(C)C)C(C)C
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1cc(Cl)ccc1OCc1cnco1)c1cnn2cccnc12

Procedure:
5-Chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine was coupled with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in presence of HBTU as described in Example 1. The product was deprotected by heating with an aqueous solution of sodium hydroxide in methanol for 2 hours. The reaction mixture was cooled; the solid formed was collected by filtration and washed with water. The crude residue was purified by flash chromatography to give 18 mg of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-(oxazol-5-ylmethoxy)-phenyl]-amide as an off-white solid. MS=370 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[CH2:22][O:21][C:20](=[O:24])[N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2COC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
To a solution of 4-(2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (43 mg, 0.13 mmol) in 2 ml anhydrous dimethylformamide was added sodium hydride (8 mg of a 60% suspension in mineral oil, 0.2 mmol) portion-wise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes, at which time the initial off-gassing ended. Benzyl bromide (0.02 ml, 0.17 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for an hour. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by prep TLC to give 33 mg of 4-(1-benzyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid (60%). MS: 424 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1([CH2:12]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:9]1([CH2:12][O:8][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:10]1
Reactant: OCC1CC1
Reactant: Nc1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 3-aminophenol (300 mg, 2.70 mmol), cyclopropylmethanol (793 mg, 11.0 mmol) and triphenylphosphine (2.90 g, 11.0 mmol) in THF (6 mL) was added dropwise diethylazodicarboxylate (1.90 g, 11.0 mmol) over a 30 min period. The mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was diluted with water, acidified with aqueous 2N HCl and extracted with ether. The aqueous phase was basified with aqueous 2N NaOH and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatograph (petroleum ether/EtOAc 15:1) to afford 3-(cyclopropylmethoxy)benzenamine as a brown oil (260 mg, 58%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[S:24])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH3:21])[NH:7][C:8](=[O:11])[C:9]=1[Br:10])([CH3:3])[CH3:2].I[CH3:29]>CO>[CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:13]=[C:14]([NH:22][C:23](=[N:25][CH2:26][CH3:27])[S:24][CH3:29])[CH:15]=[CH:16][C:17]=2[O:18][CH2:19][CH2:20][CH3:21])[NH:7][C:8](=[O:11])[C:9]=1[Br:10])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CCCOc1ccc(NC(=S)NCC)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Solvent: CO
Product: CCCOc1ccc(NC(=NCC)SC)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Yield: 85.6 %

Procedure:
The compound (2.7 g, 6 mmol) of example 35 was suspended in methanol (20 ml), and added with iodomethane (1.0 g, 7 mmol). After refluxed for 3 h, the reaction mixture was concentrated to dryness. The resultant solid was recrystallized from ethylether to obtain the title compound (2.4 g, yield: 85%). 1H NMR (DMSO-d6) δ: 7.16 (1H, d), 6.99 (1H, dd), 6.87 (1H, d), 4.00 (2H, t), 3.37 (1H, m), 2.94 (2H, q), 2.56 (3H, s), 1.74 (2H, m), 1.18 (6H, d), 1.11 (3H, t), 0.98 (3H, t).
Reaction SMILES: Cl.CO[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>CO>[NH:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:4][CH:5]=3)[O:10][C:9](=[O:14])[CH:8]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=c1cc(NC2CCNCC2)c2ccccc2o1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a 4 mL screw cap vial charged with MP-BH3CN resin (Argonaut Technologies, loading 2.32 mmol/g; 0.056 g; 2 eq.) and 6-methoxy-4-(piperidin-4-ylamino)-chromen-2-one hydrochloride (I)(0.020 g, 0.064 mmol) a solution of the corresponding aldehyde (1.5 eq.) in 1.0 mL of 1:1 MeOH:CH2Cl2(1% AcOH) was added. The resulting mixture was agitated at 60° C. for 12 h. Then, additional MP-BH3CN resin (0.028 g; 1 eq.) was added followed by a solution of the aldehyde (0.75 eq.) in 0.5 mL of the same solvent. The resulting mixture was shaken at 60° C. for additional 12 h. The reaction mixture was then filtered and the resin washed with MeOH (1 mL, twice). The filtrate and the washes were combined, evaporated in vacuo and the residual oil was purified by reverse phase HPLC (TFA method).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:54].[CH2:55]([O:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1O)[CH3:56]>>[CH2:55]([O:57][C:58]1[CH:59]=[C:60]([CH:61]=[CH:62][CH:63]=1)[O:33][CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]2[CH2:22][CH2:21][N:20]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:45])[CH2:19][CH:18]2[O:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]3[O:9][CH2:8][C:7](=[O:54])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=3[CH:12]=2)=[CH:25][CH:26]=1)[CH3:56]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21
Reactant: CCOc1ccccc1O
Product: CCOc1cccc(OCCOc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)C(=O)CO4)cc2)c1

Procedure:
Analogously to Method I, 0.420 g of benzyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[2-(toluene-4-sulphonyloxy)ethoxy]phenyl}piperidinecarboxylate and 0.124 g of ethoxyphenol are reacted. The title compound is obtained as a dark yellow oil. Rf=0.16 (1:1 EtOAc-heptane); Rt=5.68.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:27])[C:20](=O)[O:21]C(C)(C)C)=[C:15]([N+:28]([O-:30])=[O:29])[CH:14]=1)[CH:7]=[CH:6]2.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:27])[CH:20]=[O:21])=[C:15]([N+:28]([O-:30])=[O:29])[CH:14]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(-c3ccc(N(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c3)ccc2c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc2nc(-c3ccc(N(C)C=O)c([N+](=O)[O-])c3)ccc2c1
Temperature: 100 °C
Yield: 100 %

Procedure:
tert-Butyl 4-(6-methoxyquinolin-2-yl)-2-nitrophenyl(methyl)carbamate AS-5332-46: To a solution AS-5332-42 (0.030 g, 0.186 mmol) in THF (3.0 mL) was added Boc anhydride (0.063 g, 0.0.291 mmol) and DMAP (0.012 g, 0.097 mmol). The resulting reaction mixture was heated at 100° C. for 30 min. The volatiles were removed in vacuo and residue was purified on a Combiflash purification system (silica gel, 0-7% EtOAc:DCM) to afford AS-5332-43 as a off white solid (0.040 g, 100%). 1H-NMR (400 MHz, CDCl3) δ: 8.69 (d, J=2.0 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.41 (dd, J=9.2, 2.8 1H), 7.10 (d, J=2.8 Hz, 1H), 3.95 (s, 3H), 3.34 (s, 3H), 1.32 (s, 9H); MS (ESI): 410.1 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCOCC1>[CH2:13]([O:12][C:3]([CH:4]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])=[O:11])[CH:14]=[CH2:15]
Reactant: CCOC(=O)CCCCBr
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
16.29 g (407.19 mmol) of sodium hydride are added in portions to a solution of 100 g (542.92 mmol) of diallyl malonate in 900 ml of dry dioxane at 5° C. After gas evolution ceases, the reaction mixture is warmed to 40° C. and stirred for 30 min. Then 56.76 g (271.46 mmol) of ethyl 5-bromovalerate in 100 ml of dry dioxane are added dropwise, and the mixture is stirred at 110° C. for 12 hours. After the reaction is complete, the mixture is cooled to room temperature and added to about 400 ml of ice-water. After neutralization of the reaction mixture with 1 N hydrochloric acid, the organic phase is separated off, and the aqueous phase is extracted three times with 250 ml of ethyl acetate each time. After the organic phases have been combined they are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the reaction solution is concentrated in vacuo. Subsequently excess diallyl malonate is removed by high vacuum distillation (boiling point: 57° C., 0.074 mbar). The distillation residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). 73.92 g (236.65 mmol, 44% of theory) of a colorless liquid are obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([C:8]([CH3:10])=O)([CH3:7])=O>>[CH3:7][C:5]12[NH:4][CH2:1][CH2:2][NH:3][C:8]1([CH3:10])[NH:3][CH2:2][CH2:1][NH:4]2
Reactant: CC(=O)C(C)=O
Reactant: NCCN
Product: CC12NCCNC1(C)NCCN2
Yield: 37 %

Procedure:
The compound was prepared in 37% yield by reacting ethylenediamine with biacetyl according to the method of Stetter, Chem. Ber. 86, 69 (1953).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([S:19](Cl)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]>C1COCC1.C(Cl)Cl>[CH2:15]([S:19]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20])[CH2:16][CH2:17][CH3:18]
Reactant: Nc1ccncc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)Nc1ccncc1
Temperature: 50 °C
Reaction time: 19 h
Yield: 25.8 %

Procedure:
51.0 g of 4-aminopyridine (0.542 mol) and 75.0 ml of triethylamine (54.8 g, 0.542 mol) were dissolved at 50° C. in 540 ml of THF. Again at 50° C., 70.3 ml of n-butanesulphonyl chloride (84.9 g, 0.542 mol) were added dropwise to this solution over the course of 1 h. After 19 h of stirring at 50° C. the reaction mixture was diluted with 500 ml of methylene chloride and extracted twice with 500 ml of 1 N NaOH. The aqueous phase was adjusted to a pH of 6-7 with concentrated HCl and then extracted with 500 ml of methylene chloride. The organic phase was dried over magnesium sulphate and the methylene chloride was removed by distillation. The 30 g of crude product obtained were recrystallized from acetonitrile. This gave 19.0 g of clean product. The constitution of the compound was verified by NMR-spectroscopy.