Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][N:1]3[CH:2]([C:11]4[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]3=[O:7])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2[nH]ccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 1H-indole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 365.00 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>>[C:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:23])=[CH:17][CH:16]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccc2ncccc2c1
Reactant: CC(=O)c1ccc(N=C=O)cc1
Product: CC(=O)c1ccc(NC(=O)Nc2ccc3ncccc3c2)cc1

Procedure:
Prepared from 6-aminoquinoline and 4-acetylphenyl isocyanate. m/z (ES+) 306 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=[O:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:17]([F:19])[F:18]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:17]([F:19])[F:18])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: O=C1CC(c2ccc(Cl)cc2)=NO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: FC(F)Oc1cc(-c2ccc(Cl)cc2)no1
Temperature: 0 °C

Procedure:
In a 100 ml autoclave, 5.87 g (0.03 mol) 3-(4-chlorophenyl)-5-(4H)-isoxazolone was dissolved 30 ml dioxane and treated with 10 ml of 30% aqueous potassium hydroxide. The autoclave was pressurised to 10 bar with chlorodifluoromethane and the reaction mixture was heated at 50°-60° C. for 15 hours. After cooling and reducing the pressure the solution was poured into 300 ml ice/water and extracted three times with 70 ml ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by column chromatography.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[C:5]=1[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[CH2:33][C:34](Cl)=[O:35])([CH3:23])[CH3:22].CCN(CC)CC>C1COCC1>[CH3:32][CH:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]([CH3:22])[CH3:23])[C:25]=1[CH2:33][C:34]([NH:10][S:7]([CH2:6][C:5]1[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:9])=[O:8])=[O:35])[CH3:31]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Reactant: CC(C)c1cc(C(C)C)c(CS(N)(=O)=O)c(C(C)C)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CS(=O)(=O)NC(=O)Cc2c(C(C)C)cccc2C(C)C)c(C(C)C)c1
Yield: 12.1 %

Procedure:
A solution of 2,4,6 - triisopropylbenzylsulfonamide (100 mg, 0.33 mmol), 2,6-diisopropylphenylacetyl chloride (75 mg, 0.34 mmol), and Et3N (47 μL, 0.34 mmol) in 10 mL THF was stirred at room temperature overnight. The solvent was evaporated and the residue was distributed between ethyl acetate and 0.1N HCl, the organic layer was washed with brine, dried, and evaporated. The pure product (20 mg, 12%) was isolated by column chromatography (4:1 hexane:EtOAc), m/e=499; NMR (CDCl3):δ 7.05-7.4 (m, 5H), 4.25 (s, 2H), 3.95 (s, 2H), 3.45-3.6 (m, 1H), 3.0-3.15 (m, 2H), 2.85-3.0 (m, 2H), 1.05-1.4 (m, 30H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[S:35]1[CH:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36]1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:40]([C:37]3[CH:38]=[CH:39][S:35][CH:36]=3)=[O:41])=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(O)c1ccsc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)c3ccsc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(g), by condensing tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate and thiophene-3-carboxylic acid using 1,1-carbonyldiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-thiophen-3-ylcarbonyloxy-ethyl)-phenyl]-piperidine-1-carboxylate as white crystals, MS: 572 (M+H)+.
Reaction SMILES: [Li]CCCC.[C:6]1([C:12]#[CH:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.O>O1CCCC1>[C:6]1([C:12]#[C:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: ICCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C(#Cc1ccccc1)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
BuLi (33.3 mL, 50 mmol, 1.5 M) was added in drops to a magnetically stirred solution of phenyl acetylene (5.11 g, 50 mmol) in dry tetrahydrofuran (200 mL) at 0° C. in a nitrogen atmosphere. After all the BuLi had been added, the reaction mixture was stirred at 0° C. for 30 minutes. A solution of 2-(5-iodpentyloxy)tetrahydro-2H-pyrane (9) (14.91 g, 50 mmol) in dry tetrahydrofuran (100 mL) was added in drops at 0° C. Adding completed, the reaction mixture was allowed to reach room temperature in order then to be refluxed over night. The reaction was monitored by thin-layer chromatography (TLC). When all the base material had been converted, water (300 mL) was added and the aqueous phase was extracted with petroleum ether (boiling point 40-60° C.) (6×50 mL). The combined organic phases were washed with water (4×25 mL) and dried (MgSO4). Petroleum ether was distilled out on a rotary evaporator, yielding 11.6 g (85%). NMR indicated a pure product, and further purification was therefore not necessary.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH2:17]C)=[O:15])=[C:12](S(C)(=O)=O)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[CH3:23][O:24][Na]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:24][CH3:23])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1S(C)(=O)=O
Reactant: CO[Na]
Solvent: CO
Product: CCc1ccc(-c2nsc(OC)c2C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 3-(4-ethylphenyl)-5-methanesulfonyl-1,2-thiazole-4-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), methanol (15 mL), MeONa (119.47 mg, 5.00 equiv). The resulting solution was stirred for 2 h at 70° C. in an oil bath. The resulting solution was extracted with 2×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×30 mL of brine, dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 141.4 mg (crude) of methyl 3-(4-ethylphenyl)-5-methoxy-1,2-thiazole-4-carboxylate as white oil. Mass spectrum (ESI, m/z): Calcd. for C15H17NO3S, 292.1 (M+H). found 292.1.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].Cl[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(OCC)(=O)C.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[C:12]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(C)Cl
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
Potassium tert-butylate (11.22 g, 2 eq) is added to a solution of DMF (80 ml) cooled down to 0° C. A solution of 1-chloro-2-nitrobenzene (7.87 g, 1 eq) and ethyl 2-chloropropanoate (7 ml, 1.1 eq) is added dropwise over 45 minutes to the mixture whilst keeping the reaction temperature below 5° C. At the end of the addition, stirring is maintained for 2 hours at 0° C., then the mixture is hydrolyzed at this temperature with a 1N solution of hydrochloric acid and ethyl acetate is added. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: heptane/dichloromethane 8:2 to 6:4) produces the expected compound in the form of a yellow oil (8.28 g; 64% yield).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:26]([CH3:30])[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:23][CH2:30][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Br)C(=O)O
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)CCOc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Yield: 80.3 %

Procedure:
2-Benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (1.1 g, 3.5 mmol) and 2-bromopropionic acid (1.2 g, 7.8 mmol) were reacted in acetone (300 mL) in presence of potassium carbonate (2.3 g, 5.1 mmol) and potassium iodide (0.1 g, 0.6 mmol), following the procedure of Example 22 to give 1.1 g of 2-benzyloxy-5-(2-carboxy-ethoxy)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-(2-carboxy-ethoxy)-benzo[de]isoquinoline-1,3-dione (1.1 g) in the presence of 10% Pd/C (0.5 g) in DMA (20 mL) afforded 0.3 g of the title compound, mp 236-239° C.;
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:13]Cl.[C:15]([O-:18])(=[O:17])[CH3:16].[K+].CN(C=O)C>O>[C:15]([O:18][CH2:13][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: O=c1c(Br)c(CCl)nc2ccccn12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2ccccn2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (4.53 g, 15.76 mmol), potassium acetate (1.5 equiv.) and DMF (60 mL) was stirred at 40° C. for 3.5 h, at this point the reaction was completed by LCMS. The mixture was cond under reduced pressure. To the residue was added water (100 mL) and the resulting precipitate was collected by filtration, washed with water (100 mL) and dried to give the (3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid, which was carried forward without further purification: 1HNMR (400 MHz, DMSO-d6): δ 8.96-8.98 (dd,1H), 8.03-8.08 (m,1H), 7.74-7.76 (dd,1H), 7.43-7.48 (m,1H), 5.2 (s,2H), 2.1 (s,3H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:6][CH:7]([O:11][CH2:12][CH3:13])[CH2:8][CH:9]=[CH2:10])[CH3:5].N#N>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:6][CH:7]([O:11][CH2:12][CH3:13])[CH2:8][CH:9]1[CH2:3][CH2:10]1)[CH3:5]
Reactant: C=[N+]=[N-]
Reactant: C=CCC(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CCOCC
Product: CCOC(CC1CC1)OCC

Procedure:
Diazomethane (6.17 g, 147 mmol) was added dropwise to 3.02 g (21 mmol) of 3-butenal diethyl acetal in 10 ml of dry ether with intensive stirring at 0 C. Then 70 mg (0.312 mmol) of palladium (II) acetate in 50 ml of dry ether was added all at once. Then stirring at 0 C continued until the evolution of N2 ceased (10 min.). The ether was distilled off to the reduced volume of the reaction mixture ca 10 ml. The precipitate was filtered off on a fritted glass funnel and the filtrate evaporated. The crude product (2.57 g) contained 97% of the title compound (GC) and was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=[O:11].[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[CH3:8][O:9][C:10]([C:12]1[N:13]=[CH:14][N:15]([C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=1)=[O:11]
Reactant: COC(=O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Add triethylamine (1.88 mL, 13.48 mmol) to a mixture of methyl-4-imidazolecarboxylate (1.0 g, 7.93 mmol) and triphenylmethyl chloride (2.43 g, 8.72 mmol) in anhydrous acetonitrile (25 mL) over 10 min at room temperature and stir overnight. Quench with water and extract with ethyl acetate (3×). Combine the organic layers, wash with 1N hydrochloride solution, water, saturated aqueous sodium bicarbonate solution and brine sequentially, dry over sodium sulfate, and concentrate to provide the title compound 1-trityl-1H-imidazole-4-carboxylic acid methyl ester (2.8 g, 7.60 mmol).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:15]([OH:16])=[CH:14][N:13]=[CH:12][C:11]=1[OH:17])(C(C)(C)C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:26][C:27]1[C:28]([C:33]2[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][CH:34]=2)=[N:29][CH:30]=[CH:31][CH:32]=1>CN(C=O)C>[OH:8][CH2:9][C:10]1[C:11]([O:17][CH2:26][C:27]2[C:28]([C:33]3[N:37]([CH:38]([CH3:40])[CH3:39])[N:36]=[CH:35][CH:34]=3)=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:12][N:13]=[CH:14][C:15]=1[OH:16]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: CC(C)(C)[Si](C)(C)OCc1c(O)cncc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1nccc1-c1ncccc1COc1cncc(O)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyloxy)methyl)pyridine-3,5-diol (100 mg, 0.39 mmol, 2 eq.) and Cs2CO3 (381 mg, 1.17 mmol, 3 eq.) in DMF (15 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (53 mg, 0.39 mmol, 1 eq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 4-(hydroxymethyl)-5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)pyridin-3-ol (36 mg, 27%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (dt, J=33.0, 16.5 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.69 (s, 1H), 7.47 (s, 1H), 7.33 (s, 1H), 7.21 (dd, J=7.8, 4.8 Hz, 1H), 6.10 (d, J=1.8 Hz, 1H), 4.84 (s, 2H), 4.68 (s, 1H), 4.44 (sep, 6.6 Hz, 1H), 1.24 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 341.1
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH:11]C(C)=O)=[CH:10][C:4]=2[O:3]1.C[O-].[Na+]>CO>[CH3:1][C:2]1([CH3:18])[O:6][C:5]2[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)O2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc(N)c([N+](=O)[O-])cc2O1
Yield: 92.7 %

Procedure:
22.0 g of 2,2-dimethyl-5-acetamino-6-nitro-1,3-benzodioxole were boiled under reflux for 1 hour in 1.1 l of methanol containing 2.2 g of sodium methoxide (10% by weight). After evaporating the solution, the residue was dissolved in methylene chloride, filtered first through Decalit and then through silicon dioxide evaporated and crystallized from isopropanol. There were obtained 17.0 g (92.8% of theory) of 2,2-dimethyl-5-amino-6-nitro-1,3-benzodioxole of melting point 128°-129° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](OC(=O)C)(=O)[CH3:14]>>[CH3:12][O:11][C:10]1[C:2]2[N:1]=[C:13]([CH3:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(C(=O)O)c1N
Product: COc1cccc2c(=O)oc(C)nc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a 100 mL round-bottomed flask, 2-amino-3-methoxybenzoic acid (10.1 g, 60.4 mmol) and acetic anhydride (50 ml, 530 mmol) were added to give a suspension. The mixture was heated to 140° C. with stirring for 180 min. The reaction mixture was cooled to room temperature and concentrated to provide 8-methoxy-2-methyl-4H-benzo[d][1,3]oxazin-4-one (11.51 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J=6.9, 2.3 Hz, 1H), 7.52-7.42 (m, 2H), 3.89 (s, 3H), 2.39 (s, 3H); HPLC: RT=0.795 min (H2O/MeOH with TFA, Sunfire C18 2.5 μm, 2.1×30 mm, gradient=2 min, wavelength=220 nm); MS(ES): m/z=292 [M+H]+.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH:4]=[CH2:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]=[CH:2][CH2:3][CH:4]([N:11]1[C:7](=[O:17])[C:8]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:9]2[C:10]1=[O:12])[CH3:5]
Reactant: C=CCC(C)O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
To a stirred solution of 4-penten-2-ol (5.00 g, 58.1 mmol), phthalimide (8.55 g, 58.1 mmol), and triphenylphosphine (15.2 g, 58.1 mmol) in THF (40 mL), at 0° C. under nitrogen, was added a solution of diethyl azodicarboxylate (10.1 g, 58.1 mmol) in THF (20 mL) dropwise. The mixture was stirred at 0° C. (12 h) and then at 25° (12 h). The mixture was diluted with water and extracted three times with chloroform. The chloroform extracts were dried (Na2SO4), evaporated and column chromatographed on Merck silica gel 60 (70–230 mesh) with chloroform to give 8.77 g (70.2% yield) of colorless oil.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:8]=[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(Cc2ccncc2)cc1Br
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: Nc1ccc(Cc2ccncc2)cc1-c1ccc(F)c(Cl)c1

Procedure:
2-bromo-4-(4-pyridylmethyl)aniline and 3-chloro-4-fluorobenzene boronic acid were combined to form 2-(3-chloro-4-fluorophenyl)-4-(4-pyridylmethyl)aniline,
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15]([S:17][CH3:18])=[S:16])[CH3:14])[NH:11][C:10]1=[O:19])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:22][CH:23](O)[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25]>C1(C)C=CC=CC=1>[CH2:27]([O:26][C:24]([C@H:23]([N:11]1[C@H:12]([C@H:13]([C:15]([S:17][CH3:18])=[S:16])[CH3:14])[C@@H:9]([C@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:20])[CH3:21])[CH3:8])[C:10]1=[O:19])[OH:22])=[O:25])[CH:28]=[CH2:29]
Reactant: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)C(O)O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)[C@@H](O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)SC
Yield: 97.1 %

Procedure:
To a solution of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine (700 mg) in toluene (7 ml) was added allyl dihydroxyacetate (560 mg), and the mixture was heated under reflux for 3 hours. The solution was washed with water, dried, and evaporated under reduced pressure to give a mixture (903 mg) of (3S,4S)-1-[(1R)-1-(allyloxycarbonyl)-1-hydroxymethyl]-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-1-[(1S)-1-(allyloxycarbonyl)-1-hydroxymethyl]-3[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:2].Cl.N>>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:21]
Reactant: CCN(CC)CCOc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Product: CCN(CC)CCOc1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 1.85 g (6.264 mmol) N-[4-(2-diethylamino-ethoxy)-3-nitro-phenyl]-acetamide (Z31a) in semiconc. aqueous HCl was stirred for 2 h at 100° C., cooled to RT, made basic with ice and conc. aqueous ammonia and the aqueous phase was exhaustively extracted with EtOAc. The combined org. phases were washed with water and dried over sodium sulphate.
Reaction SMILES: [N:1]([O-])=O.[Na+].Cl.[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[NH:17][C:18](=[O:24])[C:19]([NH2:23])=[C:20]([NH2:22])[N:21]=1)[CH:7]=[CH2:8]>O>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[C:20]2[C:19](=[N:23][N:1]=[N:22]2)[C:18](=[O:24])[N:17]=1)[CH:7]=[CH2:8]
Reactant: C=CCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CCOc1ccccc1C1=NC(=O)C2=NN=NC2=N1
Yield: 32.2 %

Procedure:
Sodium nitrite (3 g.) was added slowly with stirring to a solution of concentrated hydrochloric acid (100 ml.) in water (100 ml.) maintained at between -5° and 0° C. by means of an ice/salt bath. 2-(2-Allyloxyphenyl)-4,5-diaminopyrimid-6-one (5.1 g.) was then added in portions during 30 minutes with stirring at between -5° and 0° C. The cooling bath was removed, and the mixture stirred at room temperature overnight. The solid which separated was filtered off and dissolved in a solution of concentrated ammonium hydroxide (10 ml.) in water (100 ml.). The solution was heated with charcoal, filtered, and the filtrate acidified with glacial acetic acid. The solid which separated was filtered off and recrystallised from methanol to give 2-(2-allyloxyphenyl)-8-azapurin-6-one (1.7 g.), m.p. 173°-175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:29]1([S:26](/[CH:24]=[CH:25]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(c2ccc(/C=C/S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), ethenesulfonylbenzene (37 mg, 0.22 mmol), Pd(OAc)2 (2 mg) and triethylamine (186 mg, 1.84 mmol) in MeCN (2 mL) is heated at 120° C. in a microwave apparatus for 15 min. The mixture is filtered, poured into EtOAc and is washed with 1N HCl and brine then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound: (M−1)−=483.