Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][O:16][CH3:17])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]([O:16][CH3:17])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: CONc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Yield: 20.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.24 g (6.00 mmol)) in DMF (8.0 ml), N-(2,4-dinitrophenyl)-O-methylhydroxylamine (0.85 g (3.99 mmol)) was added under ice-cooling with stirring. After 15 minutes' stirring under ice-cooling, p-toluenesulfonyl chloride (1.15 g (6.03 mmol)) was added. Then, the temperature of the reaction mixture was brought to room temperature and stirred at the same temperature for 18 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.30 g (21%) of the title compound as orange crystals.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([O:25][CH3:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Reactant: C1COCCN1
Product: COc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CC(=O)N4CCOCC4)CS3)cc2c1
Yield: 24 %

Procedure:
The compound (83 mg, 0.22 mmol) prepared in Example 48 and morpholine instead of methylamine were reacted according to the same procedure as Example 87 to give the title compound (24 mg, Yield 24%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:2]=1.O.[NH2:14][NH2:15]>CO>[CH3:10][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:14][N:15]=1
Reactant: CC(=O)CC(=O)c1cccnc1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1cc(-c2cccnc2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Pyridin-3-yl-butane-1,3-dione (step 1) (500 mg, 3.06 mmol) was dissolved in MeOH (20 ml). Hydrazine monohydrate (230 mg, 223 μl, 4.60 mmol) was added and the resulting mixture was stirred at RT for 1 hour. After cooling to RT, the solvent was removed in vacuo. The crude residue was dissolved in DCM, dried over (MgSO4) filtered and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][CH2:8][CH2:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:2]=1.C(N(CC)CC)C.[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>C(Cl)Cl>[C:12]1([C@H:10]2[O:11][C:26](=[O:27])[N:7]([C:3]3[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(NCC[C@H](O)c2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CC[C@@H](c3ccccc3)OC2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of (S)-3-(m-tolylamino)-1-phenylpropan-1-ol (40 mg, 0.17 mmol) in dry CH2Cl2 (1 mL) was added triethylamine (50 mg, 0.51 mmol) and bis(trichloromethyl) carbonate (20 mg, 0.067 mmol) at 0° C., and the reaction mixture was stirred overnight at room temperature. When the reaction was over, the mixture was concentrated to give the crude product, which was purified by preparative TLC (3:1 Petroleum ether/EtOAc) to give (S)-6-phenyl-3-m-tolyl-1,3-oxazinan-2-one (12 mg, 26%). 1H NMR: (400 MHz, CDCl3): δ=2.24-2.37 (m, 5H), 3.52-3.63 (m, 1H), 3.70-3.79 (m, 1H), 5.42 (dd, 1H), 7.01-7.10 (m, 3H), 7.18-7.23 (m, 2H), 7.32-7.39 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26](=[O:28])[CH3:27]>CN(C)C=O>[CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[N:12]([CH2:25][C:26](=[O:28])[CH3:27])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=S)c2[nH]cnc2n(CC)c1=O
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(=S)c2c(ncn2CC(C)=O)n(CC)c1=O
Temperature: 50 °C

Procedure:
1-n-Butyl-3-ethyl-6-thioxanthine (4 g) was dissolved in dimethyl formamide (30 ml) and a small amount of potassium carbonate was added. To this mixture, 1-bromopropan-2-one (2,7 g) was added dropwise at room temperature, with stirring. The reaction was heated at about 50° C. for two hours. The reaction mixture was then extracted with chloroform several times, the chloroform phase washed with 1N KOH and water, dried with sodium sulphate, filtered and the chloroform removed in vacuo to yield a red/brown oil which, on crystallisation in a mixture of ethylacetate/petroleum, gave 1-n-butyl-3-ethyl-7-(2-oxopropyl)-6-thioxanthine as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].F[C:14]1[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:14]1[CH:15]=[C:16]([Br:24])[CH:17]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:19]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: OCc1ccc2ccccc2c1
Product: FC(F)(F)c1cc(Br)cc(OCc2ccc3ccccc3c2)c1
Yield: 80 %

Procedure:
Using the procedure described in the first paragraph of Note e. below Table IV in Example 15, 2-naphthalenemethanol was reacted with 3-fluoro-5-trifluoromethylbromobenzene to give 3-(naphth-2-ylmethoxy)-5-trifluoromethylbromobenzene (80%), m.p. 68°-70° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.C1C(=O)[N:30](OC(ON2C(=O)CCC2=O)=O)[C:28](=[O:29])C1.N>CC#N>[NH2:30][C:28]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)=[O:29]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC(N)=O)no1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 72.9 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (310 mg, 0.88 mmol) in MeCN (10 ml) was treated with N,N-disuccinimidyl carbonate (271 mg, 1.06 mmol) and stirred at room temperature, under a nitrogen atmosphere for 4.5 hours. NH3 (0.5M in dioxan) was added forming a white precipitate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of DCM:MeOH (100:0) gradually changing to (95:5) to afford the title compound as a colourless oil (253 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([SH:36])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH3:37]N(C)C=O.[H-].[Na+].IC>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]3[C:35]([S:36][CH3:37])=[N:34][C:33]4[C:28]3=[N:29][CH:30]=[N:31][CH:32]=4)[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cn2c(CC3CCN(CCn4c(S)nc5cncnc54)CC3)nc3ccccc32)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CSc1nc2cncnc2n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred mixture of 34.5 parts of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-ethyl]-9H-purine-8-thiol and 180 parts of N,N-dimethylformamide were added portionwise 3.2 parts of a sodium hydride dispersion 50%. Upon completion, stirring was continued for 0.5 hours at room temperature. 11.5 parts of iodomethane were added dropwise. After complete addition, the whole was stirred for 1 hour. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 28.3 parts (80%) of 9-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl)methyl]-1-piperidinyl]ethyl]-8-(methylthio)-9H-purine; mp. 133.1° C. (507).
Reaction SMILES: NN.C1(=O)[N:7]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:19][C@H:18]3[C@H:13]([CH2:14][C:15]4[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=4[CH2:17]3)[CH2:12]2)C(=O)C2=CC=CC=C12.C(OCC)C>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:19][C@H:18]2[C@H:13]([CH2:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[CH2:17]2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Agent: NN
Solvent: CCO
Solvent: CCOCC
Product: NCCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Hydrazine (9 mg, 0.28 mmol) was added to a solution of 2-(3-Phthalimido-n-prop-1-yl)-cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (50 mg, 0.14 mmol) in 1 mL of ethanol, and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, and 5 mL of diethyl ether was added with stirring. After 30 minutes, a white solid had precipitated. The solid was collected by filtration, rinsed with diethyl ether, then stirred in 10 mL of chloroform. The solids were filtered and washed with chloroform. The filtrate was concentrated to yield 20 mg of a colorless oil as product. Yield=63%. NMR (300 MHz, CD3OD) δ7.09-7.05 (m, 4H), 3.03-2.97 (m, 2H), 2.77-2.70 (dd, 2H, J=6 Hz, 14 Hz), 2.68-2.58 (m, 4H), 2.50-2.44 (dd, 2H, J=5 Hz, 14 Hz), 2.30 (t, 2H, J=7 Hz), 1.82 (t, 2H, J=7 Hz), 1.61 (tt, 2H, J=7 Hz, 8 Hz, 7 Hz).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])OCC)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][NH:24][CH3:25]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:24]([CH2:23][CH:22]([O:26][CH3:27])[O:21][CH3:20])[CH3:25])=[O:19])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Nc1ccc(Cc2ccccc2)cc1
Reactant: CNCC(OC)OC
Solvent: Cc1ccccc1
Product: COC(CN(C)C(=O)Nc1ccc(Cc2ccccc2)cc1)OC

Procedure:
Ethyl [4-(phenylmethyl)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(phenylmethyl)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH2:44][CH2:45][F:46])[C:36]=1[F:47])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:47][C:36]1[C:37]([O:43][CH2:44][CH2:45][F:46])=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCF)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCF)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After adding 1.09 g of 2-hydrazinopyrimidine [CAS No. 7504-94-1] and 1.37 ml of triethylamine to a solution of 5.0 g of {2-[2-fluoro-3-(2-fluoroethoxy)-5-methoxyphenyl]-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 50 ml of DMF, the mixture was stirred at 85° C. for 20 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 30 ml of methanol, 10 ml of THF and 3 ml of acetic acid. Next, 2.0 g of sodium cyanotrihydroborate was added to the solution, and after stirring at room temperature for 3 hours, 1.0 g of sodium cyanotrihydroborate was further added and stirring was continued for 2 hours and 30 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, and the insoluble portion was filtered off to give the title compound as a white solid. The filtrate was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (total: 4.88 g) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.C(N(C(C)C)C(C)C)C>ClCCl>[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[CH2:15]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (7.88 ml) was added over ten minutes to an ice-cold solution of 3-hydroxymethyl piperidine (5.76 g) and ethyldiisopropylamine (9.58 ml) in dichloromethane (300 ml). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction was then diluted with dichloromethane (500 ml), washed with 1N aqueous hydrochloric acid (200 ml), dried over magnesium sulphate, and evaporated to afford benzyl 3-(hydroxymethyl)-1-piperidinecarboxylate as an oil (12.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[Cl-].[Al+3].[Cl-].[Cl-].[Al].[CH2:16]=[CH2:17]>>[CH2:16]([C:10]1[C:2]([NH2:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH2:5][CH2:4]2)[CH3:17]
Reactant: C=C
Reactant: Nc1cccc2c1CCC2
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Product: CCc1ccc2c(c1N)CCC2
Temperature: 300 °C

Procedure:
A mixture of 106 g (0.8 mole) of 4-amino-indane, 4 g of aluminium chloride and 1.6 g of aluminium shot is heated in an autoclave to 300°C. After injection of ethylene at 200 bar, the reaction mixture is maintained for one hour at 300°C. By distillation of the green-black crude product in high vacuum there is obtained 106.9 g of 5-ethyl-4-amino-indane, B.P. 72 to 74°C/0.001 Torr.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:14]1)[CH2:7]2.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1[C:18](=[O:19])[CH:17]=[CH:16][C:15]([CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:14]1)[CH2:7]2)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)nn1CC1CCc2c(O)cccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCC(Cn1nc(C(c3ccccc3)c3ccccc3)ccc1=O)C2
Yield: 84.1 %

Procedure:
A suspension of 2-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (425 mg), ethyl bromoacetate (184 mg) and potassium carbonate (152.9 mg) in acetonitrile (15 ml) was refluxed for 6 hours. After cooling, the precipitated solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 2-[(1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxy-2-naphthyl)methyl]-6-diphenylmethyl-3(2H)-pyridazinone (0.43 g) as pale yellow oil.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)=[CH2:9].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>O>[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])=[CH:12][CH:11]=1)=[CH2:9]
Reactant: C=Cc1ccc(CO)cc1
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(COCCCCCCBr)cc1
Yield: 58 %

Procedure:
A DMF suspension (5 ml) of sodium hydride (50% in oil, 240 mg, 5.0 mmoles) was cooled to 0° C. under an argon atmosphere, and a DMF (1 ml) solution of 1.34 g of 4-vinylbenzyl alcohol (10 mmoles) was added. The reaction mixture was agitated for fifteen minutes, and a DMF solution (3 ml) of 3.66 g of 1,6-dibromohexane (15 mmoles) was added over at least five minutes. The reaction mixture was agitated at room temperature for three hours. Fifteen milliliters of water was added to the reaction solution while cooling using ice, and the solution was agitated for five minutes. The solution was extracted using ethyl acetate (2×40 ml). The combined organic layers were washed using 15 ml of saturated aqueous saline solution and dried using anhydrous sodium sulfate. Upon filtration and concentration, 4.11 g of the residue was purified using silica gel column chromatography (70 g silica gel, 20:1 hexane/Et2O) and 1.72 g of 6-(4-vinylbenzyloxy)bromohexane (5.8 mmoles, 58%) was obtained in the form of an oily substance.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.CI>CN(C)C=O>[CH3:1][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([F:7])=[N:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(F)nc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A round bottom flask was charged with K2CO3 (191 g, 1380 mmol), 6-fluoronicotinic acid (77.8 g, 551 mmol) and dimethylformamide (551 mL). Methyl iodide (51.5 mL, 827 mmol) was then added in one portion at room temperature and mixture stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed three times with water and once with brine, and then dried over Na2SO4. Purification by silica gel flash chromatography (ethyl acetate/dichloromethane) gave 6-fluoro-nicotinic acid methyl ester (71.8 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 3.96 (s, 3 H) 7.01 (dd, J=8.58, 2.93 Hz, 1 H) 8.41 (ddd, J=8.49, 7.61, 2.44 Hz, 1 H) 8.89 (d, J=2.34 Hz, 1 H); MS (M+1): 156.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-:3])=[O:2].[Hg](C#N)C#N.[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@@H:21]1Br)(=[O:18])[CH3:17]>>[C:16]([O:19][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:23][S:22][C@H:21]1[S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:18])[CH3:17]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: O=[N+]([O-])c1ccccc1S
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2[N+](=O)[O-])SC[C@H]1OC(C)=O
Yield: 48 %

Procedure:
If the procedure described in Preparation I is followed starting from 6 g (38.7.10-3 mol) of 2-nitrobenzenethiol, 10.75 g (42.5.10-3 mol) of mercuric cyanide, Hg(CN)2, and 15.12 g (42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 8 g (yield: 48%) of the expected product are obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC1C=CC=C2C=1COC2=O>C(Cl)(Cl)(Cl)Cl>[C:12]([C:11]1[CH:16]=[CH:17][C:18]([CH2:20][Br:1])=[CH:19][C:10]=1[CH3:9])([O:14][CH3:15])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1C
Agent: Cc1cccc2c1COC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1C

Procedure:
N-Bromosuccinimide (44.9 g) was added to a solution of methyl 2,4-dimethylbenzoate (41.36 g) in carbon tetrachloride containing a trace of dibenzoyl peroxide. The mixture was heated under reflux until no orange colour persisted then cooled, filtered and the filtrate evaporated to leave an oil. This was distilled until ~16 g distilate bp 98°-140°/0.8-5 mm (starting material) had been collected. The residue was then heated at atmospheric pressure until no more methyl bromide was evolved, to give a mixture of the title compound and 4-methylphthalide. Addition of hot petrol and filtration from the phthalide gave after evaporation the title compound. τ (CDCl3) 7.48 (3H, s), 6.21 (3H, s), 5.65 (2H, s), 2.6-2.93 (2H, m), 2.18 (1H, d, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:35][C:34]([CH3:37])([CH3:36])[C:33]2[C:28](=[CH:29][C:30]([NH2:38])=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([O:23][C:24]([N:26]1[CH2:35][C:34]([CH3:37])([CH3:36])[C:33]2[C:28](=[CH:29][C:30]([NH:38][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=3)=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C(C)(C)C1
Reactant: O=C(O)c1ccccc1NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3ccc(F)cc3)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of 2-(4-fluorobenzylamino)benzoic acid (Step A, 0.7 g, 1.20 mmol), 7-amino-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (0.71 g, 2.57 mmol), TBTU (0.917 g, 2.86 mmol), and DIEA (0.5 mL) in 30 mL of CH2Cl2 was stirred at RT for 2 h, then diluted with more CH2Cl2. The organic layer was washed with water, and brine, dried with MgSO4, filtered, and condensed. The residue was purified by flash column chromatography (0 to 30% of EtOAc in CH2Cl2), and the titled compound was obtained as oil. MS (ES+): 504 (M+H)+. Calc'd for C30H34FN3O3-503.26.