Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClC(Cl)Cl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CO)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred mixture of 67 parts of 4-piperidinemethanol, 61 parts of N,N-diethylethanamine and 750 parts of trichloromethane there were added dropwise 64.5 parts of ethyl chloroformate. Stirring was continued for 2 hours at reflux temperature. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated, yielding 75 parts (70%) of ethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (interm. 50).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[OH:10]O>C(O)(=O)C.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:8]=[N+:7]([O-:10])[C:6]([CH3:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(C)nc1
Reactant: OO
Agent: O=[Mn]=O
Solvent: CC(=O)O
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 5-methoxy-2-picoline from Step 1 (6.7 g) was treated with 30% H2O2 (6.12 mL) in acetic acid (40 mL) at 100° C. overnight. After cooling to r.t., excess MnO2 was added and the slurry was stirred for 2 hours. Filtration and concentration in vacuo gave 7.0 g of the title N-oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[C:14](=[O:15])[CH:13]=[CH:12][NH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:19]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][N:20]=1>CS(C)=O.CCOC(C)=O>[I:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([N:11]2[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=3)=[CH:10]2)[CH:24]=1
Reactant: Fc1cc(I)ccn1
Reactant: COc1ccc(COc2c[nH]ccc2=O)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3cc(I)ccn3)ccc2=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one (7.30 g, 31.6 mmol), 2-fluoro-4-iodopyridine (10.56 g, 47.35 mmol), and K2C03 (10.9 g, 79 mmol) in DMSO (80 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2S04), filtered and concentrated. The residue was washed with EtOAc and filtered, and the collected solid dried to give 4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one. 1H-NMR (DMSO, 400 MHz) (5 8.41 (dd, J=8.0, 2.4 Hz, 1H), 8.30 (s, 1H), 8.20 (m, 2H), 7.81 (dd, J−4.0, 0.8 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 6.28 (d, J=7.6 Hz, 1H), 4.96 (s, 2H), 3.72 (s, 3H). MS (M+H)+ 435.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1cccc(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-bromophenol (27.4 g, 158 mmol) in CH2Cl2 was added chloromethyl methyl ether (18 mL, 237 mmol). The reaction mixture was cooled to 0° C. and diisopropylethylamine (55 mL, 316 mmol) was added and the cold bath was removed. The reaction mixture was stirred for 3 hours at ambient temperature and then poured into 10% aqueous HCl. The layers were separated and the aqueous phase was extracted 4 times with CH2Cl2. The combined organic layers were washed once each with saturated aqueous NaHCO3, 15% aqueous NaOH, and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide 3-methyloxymethoxy-bromobenzene as a yellow oil.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].Cl[CH:8]([Cl:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O>O1CCCC1>[Cl:16][C:8]1([O:5][C:4]1([CH:1]([CH3:3])[CH3:2])[CH3:6])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Reactant: CC(=O)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1(C)OC1(Cl)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of 122 g of potassium tert.-butylate in 720 ml of tetrahydrofuran was added with stirring under an inert atmosphere at -20°C to a mixture of 95 g of methyl isopropyl ketone and 185 g of tert.-butyl dichloroacetate and the mixture was allowed to return to room temperature and was stirred for 2 hours. The mixture was poured into iced water and stirred after which the organic phase was removed, washed with aqueous sodium chloride solution and dried over magnesium sulfate. After passing the solution through vegetable black, the solution was concentrated to dryness to obtain 230.4 g of tert.-butyl 2-chloro-2,3-epoxy-3-isopropyl-butanoate in the form of a colorless liquid soluble in the usual organic solvents and insoluble in water.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=O)[NH:12][N:13]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc(-c2ccccc2O)n[nH]1
Product: Oc1ccccc1-c1ccc(Cl)nn1

Procedure:
Preferably, in the present process, the 6-(2-hydroxyphenyl)-3(2H)-pyridazinone is added to a cold mixture of phosphorus oxychloride and the disubstituted formamide. The reaction mixture is then heated to about 75°-90° C. for about 4-5 hours. The product is isolated from the reaction mixture by methods known to the art for example by cooling the reaction mixture, quenching in cold water, preferably below 40° C., and filtering to give the 3-chloro-6-(2-hydroxyphenyl)pyridazine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[C:17]([CH:23]=O)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:23][C:17]1[C:16]([CH3:15])=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNCCCCN(C)C(=O)OC(C)(C)C)c(C)c1

Procedure:
Using General Procedure B: Reaction of (4-Amino-butyl)-methyl-carbamic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20](OC)=[O:21].CC(C)([O-])C.[K+]>>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:20][OH:21]
Reactant: COC=O
Reactant: COC(=O)Cc1cc(Cl)ccc1Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1

Procedure:
Example 8 of the European Patent EP 1710241 B1 also describes an alternative process for the synthesis of the lactam (VI), see Scheme 4. In this example, (5-chloro-2-phenoxyphenyl)acetic acid methyl ester (compound VIIIa) is reacted with methyl formate in the presence of potassium tert-butoxide to give 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylic acid methyl ester (compound IXa, E/Z mixture 9:1), which is directly cyclized with pyrophosphoric acid to obtain methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa), referred to us 8-chlorodibenzo[b,f]oxepin-10-carboxylic acid methyl ester in EP 1710241 B1, with 85% yield. This compound is then reacted with nitromethane in the presence of tert-butyl-tetramethylguanidine to give methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), referred to us 8-chloro-1′-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, with a trans to cis ratio of 8:1, which is directly hydrogenated in the presence of a sponge nickel catalyst to give methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), referred to us 11-aminomethyl-8-chloro-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, which after treatment with potassium tert-butoxide and dimethyl sulphate, is converted into the lactam (VIa) with an overall yield of 81% from compound (Xa), but predominantly corresponding to the undesired cis-isomer (approximately 85:15 ratio with respect to the trans-isomer), being therefore necessary to carry out one of the above described low-yield processes for the conversion of undesired cis-(VI) to trans-(VI).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]([C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)([CH3:8])[CH3:7].[Br:14]Br>C(O)(=O)C.O>[Br:14][C:13]1[C:9]([CH:6]([CH3:8])[CH3:7])=[N:10][NH:11][CH:12]=1
Reactant: CC(C)c1cc[nH]n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1n[nH]cc1Br
Reaction time: 15 h
Yield: 80.9 %

Procedure:
To a stirred solution of sodium acetate (19.7 g., 0.24 mole) in acetic acid (100 ml.) and water (15 ml.), 3-isopropylpyrazole (11.0 g., 0.1 mole) was added, followed by dropwise addition of bromine (16.0 g., 0.11 mole) keeping the internal temperature below 15° C. The mixture was kept at 25° C. for 15 hours, treated with water (200 ml.) and extracted with ethyl ether (3 × 50 ml.), and the ether layer washed with water (1 × 50 ml.) dried, (sodium sulfate) and evaporated under reduced pressure. The resultant pale yellow oil was distilled to give 4-bromo-3-isopropylpyrazole (15.3 g., 81%) with a boiling point of 85° C. at 0.06 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:14]Br.[OH-].[Na+]>C(O)(=O)C>[Br:14][C:4]1[N:3]=[C:2]([F:1])[C:7]([NH2:8])=[CH:6][CH:5]=1
Reactant: Nc1cccnc1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc(Br)nc1F
Temperature: 2.5 °C
Yield: 76.4 %

Procedure:
To a stirred solution of 2-fluoro-pyridin-3-ylamine (3.0 g, 26.79 mmol) in acetic acid (24 mL), sodium acetate (2.17 g, 26.46 mmol) was added. The reaction mixture was cooled to 0-5° C. and a solution of bromine (1.37 mL, 26.74 mmol) in acetic acid (8 ml) was added dropwise. After 1 hour the reaction mixture was cooled to 0° C., 10% aqueous sodium hydroxide solution was added to adjust the pH ˜5 and the product was extracted with ethyl acetate (200 mL). The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ethyl acetate in hexane to afford 6-bromo-2-fluoro-pyridin-3-ylamine (3.9 g) as a brown solid. 1H NMR (400 MHz, CDCl3) δ: 7.15 (d, J=7.8 Hz, 1H), 7.00 (dd, J=10.1, 7.8 Hz, 1H), 3.80 (s, 2H). ESMS: m/z 191.32, 193.34 [M+1]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].[CH2:14]([O:16]C(=O)OCC)C.Cl>C1C=CC=CC=1>[OH:9][C:8]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[O:11][C:14](=[O:16])[CH:10]=1
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc2c(O)cc(=O)oc2c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A solution of 42 g (0.28 mol) of 2-hydroxy-4-methylacetophenone in benzene (150 mL) was added over 30 min. to a suspension of NaH (50% oil), 30 g, 0.63 mol) in 400 mL of benzene at reflux. Then, diethylcarbonate (67.8 mL, 0.56 mol) in benzene (500 mL) was added over 15 min. The reaction mixture was refluxed for 16 s h and more NaH (13 g, 0.28 mol) was added followed by more diethylcarbonate (33 g, 0.28 mol). After another 6 h at reflux the reaction mixture was cooled to r.t. and HCl (2N) was added (1.5 L) to form a white precipitate. The solid was then filtered and added to a solution of NaOH (4N) (800 mL). The resulting basic solution was then extracted with Et2O (2×500 mL) and the basic solution acidified with HCl conc. to give a white solid which after filtration and dried gave 38.7 g (79%) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.O>[I:7][C:8]1[CH:9]=[N:10][N:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:12]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of cesium carbonate (20.7 g, 63.4 mmol) and 4-iodopyrazole (10.00 g, 51.6 mmol) in DMF (100 mL) was allowed to stir for 10 min. To the mixture was added 2-(2-bromoethoxy)tetrahydro-2 h-pyran (9.98 ml, 63.4 mmol) and heated at 80° C. overnight. The mixture was diluted with water and extracted with EtOAc (3×50 mL), and subsequently washed with water (2×50 mL) and brine, dried over sodium sulfate, and filtered. The crude mixture was evaporated onto silica gel and purified via MPLC (0% to 50%; EtOAc in hexanes). Isolated 4-iodo-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole (15.3 g, 92%) as a clear oil. MS m/z=323.0 [M+1]+. Calc'd for C10H15IN2: 322.1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a mixture of 4-iodopyrazole (Aldrich, Buchs, Switzerland, 10 g, 51.6 mmol) and Cs2CO3 (20.16 g 61.9 mmol) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (Aldrich, Buchs, Switzerland, 9.74 ml, 61.9 mmol). The RM was stirred at 70° C. for 17 h. Then the RM was quenched with water (100 ml) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (hexane/EtOAc 0% to 30%). The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil. (HPLC: tR 3.12 min (Method A); M+H=323 MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[CH2:15]([O:18][CH2:19][C:20](N(OC)C)=[O:21])[CH:16]=[CH2:17].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:18][CH2:19][C:20]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[F:8])=[O:21])[CH:16]=[CH2:17]
Reactant: Fc1ccc(Br)cc1I
Reactant: C=CCOCC(=O)N(C)OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOCC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Scheme 1, steps C and D: To 4-bromo-1-fluoro-2-iodobenzene (0.95 equiv.) in THF (4.6 mL/g) at 0° C. is added isopropylmagnesium chloride (1.0 equiv, 20 weight percent in THF). After about 60 minutes at 0° C., a solution of 2-(allyloxy)-N-methoxy-N-methylacetamide (1.0 equiv.) (Volumes for this stage are in mL/g of this compound) in THF (2.2 mL/g) is added over about 60 minutes. The reaction mixture is quenched into a solution of NH4Cl (4.3 equiv.) in water (5.8 mL/g) at 0° C. Heptanes (7.2 mL/g) is added as the mixture is warmed to room temperature, and the layers are separated. The organic layer is washed with water (7.2 mL/g). The organic layer is concentrated while additional heptanes (4 mL/g) is added to remove water and THF. The intermediate, 2-allyloxy-1-(5-bromo-2-fluoro-phenyl)ethanone is obtained as a solution in heptanes (approximately 20-25 weight %).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH2:21][CH2:22][CH3:23]>>[CH2:21]([C:20]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:22][CH3:23]
Reactant: CCCC(OC)(OC)OC
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Product: CCCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Yield: 80.3 %

Procedure:
The general method described in Step 3 of Example 15 was used to cyclize ethyl 3-(3-aminoquinolin-4-ylamino)propionate (11.0 g, 42.4 mmol) by reaction with trimethyl orthobutyrate (7.22 g, 48.7 mmol) to provide ethyl 3-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propionate (10.6 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:11][OH:12].[OH-].[Na+]>CO>[C:1](=[N:11][OH:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Acetophenone (5.0 mL, 43 mmol) was dissolved in methanol (50 mL). Hydroxylamine hydrochloride (6.1 g, 88 mmol) was added to the mixture followed by 10N sodium hydroxide (10 mL, 100 mmol). Reaction was stirred at room temperature for 20 minutes. 10N Sodium hydroxide (5 mL, 50 mmol) was added to the mixture. Reaction was heated at reflux for 1 hour. Mixture was cooled to room temperature and stirred for 4 hours. Reaction mixture was concentrated in vacuo. Residue was treated with water. Mixture was extracted 2× diethyl ether. Combined extracts were washed 1× water, 1× brine. Organic layer was dried (magnesium sulfate), filtered and concentrated. Title compound was obtained as white solid in 76% yield. MS m/e (M+H)+=136.0.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:38][CH2:39]OC(C)=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:38]=[CH2:39])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (16a) (9.5 g, 18.9 mmol), tetrakis(triphenylphosphine) palladium(0) (1.0 g, 0.9 mmol), (2-ethenyl)tri-n-butyltin (11.0 mL, 37.8 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (16b) (7.7 g). MS m/z: [M+H+] calcd for C26H27FN2O4, 451.2; found 451.0. 1H-NMR (CDCl3): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01 (2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>[OH-].O1CCOCC1>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nc1cnc2c(n1)CCNCC2
Agent: Br
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cnc2c(n1)CCN(C(=O)Cc1ccc(Cl)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.8 gm (17.9 mmols) of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide were dissolved in 50 ml of 2N hydroxide, and the solution was admixed dropwise with an ice-cooled solution of 7.5 gm of p-chlorophenyl-acetyl chloride in 50 ml of dioxane. The resulting mixture was stirred overnight and then evaporated, and the residue was extracted with chloroform. The chloroform extract was dried and then evaporated, and the residue was triturated with carbon tetrachloride and suction-filtered.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:19][CH:9]2[CH2:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:2][CH3:3]>ClCCCl.C(O)(=O)C.[O-2].[O-2].[Mn+4]>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:19][C:9]2=[CH:10][NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:7]([C:8]=32)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2c(C(N)=O)ccc3c2C(CN3)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2c[nH]c3ccc(C(N)=O)c(c23)C1
Reaction time: 2.5 h
Yield: 97.5 %

Procedure:
Manganese dioxide (43.3 g, 498 m moles) was suspended in 1,2-dichloroethane (400 ml) in a 2-liter flask. The manganese dioxide suspension was cooled to -5° C., and acetic acid was added to the flask (300 ml). The manganese dioxide suspension was again cooled to -5° C. 4-(di-n-propyl)amino-6-aminocarbonyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole (100 g, 332 m moles) was dissolved in acetic acid (300 ml). The solution was added to the manganese dioxide suspension while the temperature was maintained between -6° and 0° C. The reaction mixture was stirred for 2.5 hours. Filter aid (45 g) was added to the reaction mixture, which was then filtered. The filter cake was washed with acetic acid (600 ml) and dichloroethane (800 ml). The filtrate was evaporated in vacuo. The residue was taken up in toluene (500 ml), and the solution was evaporated in vacuo. The residue was again taken up in toluene (500 ml), and the solution was evaporated in vacuo. To the residue (186 g) was added aqueous sodium hydroxide (2.0 N, 700 ml). The mixture was stirred for 30 minutes, and filter aid (45 g) was added to the mixture. The mixture was filtered, and the filter cake was washed with 1,2-dichloroethane (500 ml). The organic phase of the filtrate was washed with water (700 ml), washed with saturated sodium chloride (700 ml), and then dried over sodium sulfate. The solvent was evaporated in vacuo to afford 96.8 g of the desired compound which was identified by comparison of nmr spectrum with the known compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
A stirred, cloudy solution of 3-bromo-5-iodobenzoic acid (10 g, 30.59 mmol) and concentrated sulfuric acid (0.60 mL) in MeOH (65 mL) was heated under reflux for 15 h. The resulting clear, light yellow solution was then allowed to cool to room temperature and was concentrated under vacuum. The residual yellow solid was dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (10 g, 96% yield) as a light yellow solid: 1H NMR (CD3OD, 500 MHz) δ ppm 3.93 (3H, s), 8.12 (1H, m), 8.15 (1H, m), 8.29 (1H, m). HPLC retention time: 2.335 min (method A). MS (ESI) (M+H)+ 340.00.