Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19].S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:11]=1[O:12][CH3:13])[C:6]([Cl:8])=[O:7].[CH3:20][C:17]1([CH3:21])[CH2:18][O:19][C:6]([C:5]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:16]1
Reactant: CC(C)(N)CO
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cc(C2=NC(C)(C)CO2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 16.2 g (70 mmoles) of 3,4,5-trimethoxybenzoyl chloride (compound 1) in 40 ml of dry methylene chloride was added dropwise to a solution of 12.5 g (140 mmoles) of 2-amino-2-methyl-1-propanol in 50 ml of dry methylene chloride under cooling in an ice-bath for 30 minutes. After completion of the addition, the mixture was stirred for additional 45 minutes and the reaction solution was filtered through a glass filter. The filtered cake was washed with methylene chloride and the filtrate was combined with the washing, which was followed by concentration in vacuo. The residue was dissolved in 30 ml of dry toluene, and 6.64 ml (91.0 mmoles) of thionyl chloride was added dropwise thereto under cooling in an ice-bath. The mixture was allowed to warm to room temperature, while being stirred for additional 45 minutes. Subsequently, 20 g of ice and aqueous sodium hydroxide (18 g of NaOH in 60 ml of water) were added to the mixture and then the mixture was extracted with toluene. The extract was washed with water and brine and dried over anhydrous magnesium sulfate. After concentration in vacuo, the residue was crystallized from 70 ml of n-hexane to give 16.8 g (90.6% from compound 1) of the desired compound. Melting point: 87°-89° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:24]COC(C)=O.CCCCCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:24])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCO[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
50 g (1 eq) tert-butyl 3-(tert-butyldimethylsilyloxy)propylcarbamate dissolved in 200 ml THF were added dropwise to a mixture of 20.7 g (5 eq) sodium hydride and 300 ml THF at 0° C. After heating the reaction mixture to 10° C., 32.3 ml (3 eq) methyl iodide were added dropwise. On completion of the addition, the mixture was stirred for 3 h at room temperature. The reaction course was monitored by thin-layer chromatography (30% EtOAc/hexane). Once the conversion was complete, the reaction mixture was quenched with saturated NH4Cl solution and then extracted with ethyl acetate. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 48 g (92%) of product were obtained in the form of an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:17]([F:28])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)=[C:17]([F:28])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:29])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)c(F)c3nc21
Yield: 67.2 %

Procedure:
A suspension of 0.8 g of 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine in 20 cm3 of ethanol and 20 cm3 of N aqueous potassium hydroxide solution is heated at a temperature close to 75° C. for 1 hour and a half. 12 g of a 10% aqueous acetic acid solution are added to the solution obtained, at this temperature. The insoluble matter obtained is drained at about 75° C. and washed 3 times with 30 cm3 of water at about 20° C. After recrystallizing once from 90 cm3 of dimethylformamide, 0.5 g of 7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 345°-347° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15]1([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([OH:32])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>FC(F)(F)C(O)=O.O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:23]3[O:22][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:25][C:24]=23)=[O:31])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12].[NH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:23]3[O:22][C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:25][C:24]=23)=[O:32])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc3oc(-c4ccccc4)nc23)CC1
Product: O=C(NC1CCNCC1)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 4-amino-1-tert-butyloxycarbonylpiperidine and 2-phenylbenzoxazole-4-carboxylic acid using the coupling method described in Step C of Example 7. This crude material was immediately dissolved in a mixture of trifluoroacetic acid (1.0 mL) and water (0.05 mL) and the resulting solution stirred at ambient temperature for 0.5 hours. The reaction was then concentrated to dryness in vacuo. The resulting oil was purified using preparative HPLC to afford a 74% yield of N-(piperidin-4-yl)-2-phenylbenzoxazole-4-carboxamide as a white solid: mp 99-102° C.; 1H NMR (500 MHz, CD3OD) δ 8.27 (dd, J=7.5, 2.0 Hz, 2H), 7.89 (dd, J=8.0, 1.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.65-7.58 (m, 3H), 7.49 (t, J=8.0 Hz, 1H), 4.20-4.14 (m, 1H), 3.26 (d, J=13.0 Hz, 2H), 2.90 (t, J=12.0 Hz, 2H), 2.16 (d, J=12.5 Hz, 2H), 1.75 (q, J=12.5 Hz, 2H); MS (ESI) m/z 322 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[NH:13][N:14]=[C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:21]([O:23]C)=O.C(O)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[N:13]1[C:21](=[O:23])[N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:15]2=[N:14]1
Reactant: C#CCOc1cc(NN=C2CCCCN2C(=O)OC)c(Cl)cc1Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C#CCOc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl
Temperature: 100 °C
Yield: 87.6 %

Procedure:
A mixture of 10.0 g of the product from Step B and 0.50 g of glacial acetic acid in 50 mL of toluene is heated at 100° C. for 2 h while removing methanol vapor with a stream of nitrogen. Hexane (50 mL) is added at 70° C. and the product is filtered at 25° C. and washed with hexanes to provide 8.0 g (94%) of the title compound, m.p. 168°-169° C. 1H NMR (CDCl3) δ1.9 (m, 4H), 2.55 (t, 1H, J=2.4Hz), 2.74 (t, 2H, J=6Hz), 3.67 (t, 2H, J=6Hz), 4.74 (d, 2H, J=2.4Hz), 7.13 (s, 1H), 7.50 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[CH:22]=[O:23])[N:15]=2)[NH:10][C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(=CC)C.[O-:33]Cl=O.[Na+]>CC(O)(C)C>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[C:21]([CH:24]=3)[C:22]([OH:33])=[O:23])[N:15]=2)[NH:10][C:9]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(-c2cnc3[nH]c(=O)n(Cc4ccccc4)c3n2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-methoxybenzaldehyde (296 mg, 0.82 mmol) in t-BuOH (18.2 mL) was sequentially added saturated aqueous NaH2PO4 solution (4.1 mL), 2-methyl-2-butene (2M in THF, 3.92 mL) and NaClO2 (114.8 mg). The mixture was stirred at room temperature for one hour, and then concentrated under reduced pressure. The residue thus obtained was purified by column chromatography [silica gel; MeOH/DCM (1:9)] to give the product as white powder (244 mg, 65%). 1H NMR (400 MHz, DMSO): δ 8.44 (s, 1H), 8.19 (s, 1H), 8.08 (d, J=9.2 Hz, 1H), 7.40-7.26 (m, 5H), 7.18 (d, J=8.8 Hz, 1H), 5.05 (s, 2H), 3.84 (s, 3H). MS: 377.0 (M+H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][C:9](=[O:13])[O:10][CH2:11][CH3:12]>>[CH3:7][O:6][C:1](=[O:5])[CH:2]=[CH2:3].[CH2:11]([O:10][C:9](=[O:13])[CH:8]=[CH2:1])[CH3:12].[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(C)=O
Agent: C=C(C)C(=O)OC
Product: C=CC(=O)OC
Product: C=CC(=O)OCC

Procedure:
A degassed solution of the MA-EA diblock of Example 36 (80 mg) and di-t-butylnitroxide (0.025 mg) in methyl methacrylate (2 ml) was heated at 100° C. for 0.5 hr. The 1H NMR of the product (220 mg), obtained on evaporation of volatiles, indicated that approx. 60 methyl methacrylate units per chain on average, had added onto the MA-EA diblock to give the triblock of structure 37. 1H NMR (250 MHz) δ: 1.10 and 1.11 (O-t-butyl), 3.60 (COOCH3 of MMA), 3.68 (COOCH3 of MA), 4.0-4.2 (O--CH2CH3), 7.1-7.35 (ArH). The N-t-butyl signals of the starting material were no longer present. GPC: Mn =10500 (Mw /Mn =2.6) confirmed the expected increase in chain length.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].C(N(CC)CC)C.[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>CN(C=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NCC1COc2ccccc2O1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)NCC1COc2ccccc2O1
Reaction time: 3 h

Procedure:
Racemic 2,3-dihydro-1,4-benzdioxin-2-ylmethylamine (8.25 g, 5.0 mmol) and triethylamine (1.52 g, 15 mmol) were combined in DMF (10 mL) and cooled in an ice bath as dimethylsulfamoyl chloride (1.44 g, 10 mmol) was added. The reaction mixture was then stirred for 3 hr with continued cooling. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate solution was washed with brine, dried (MgSO4) and evaporated in vacuo to yield an oil. The oil was purified using flash column chromatography (ethyl acetate:Heptane—1:1) to yield a white solid, which was recrystallized (ethyl acetate/Hexane) to yield the title compound as a white floccular solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:10])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@](C)(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@](C)(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
630 mg (2.374 mmol) of N-(tert-butoxycarbonyl)-2-phenyl-D-alanine were dissolved in 20 mL of dry DMF and O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU, 1.37 g, 4.27 mmol), morpholine (0.412 mL, 4.73 mmol) and diisopropylethylamine (1.63 mL, 9.5 mol) were added. The mixture was stirred at room temperature for 1 hour, then the solvent was removed and the residue dissolved with dichloromethane. The solution was washed with saturated NaHCO3, brine, water and dried over Na2SO4. 700 mg of the title compound were recovered (88% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:11][C:12]1[CH:17]=[C:16](B(O)O)[CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([F:11])[CH:17]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: OB(O)c1ccnc(F)c1
Reactant: N#Cc1cc(Br)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: N#Cc1cc(Br)ccc1-c1ccnc(F)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added 5-bromo-2-iodobenzonitrile 206-1 (500 mg, 1.6 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (229 mg, 1.6 mmol), Pd(PPh3)4 (94 mg, 0.08 mmol), Na2CO3 (516 mg, 4.9 mmol), toluene (2 mL), H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120° C. overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 5-bromo-2-(2-fluoropyridin-4-yl)benzonitrile 206-3. MS m/z 277.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:34][C:35]([F:53])([F:52])[O:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[C:48]3[CH:49]=[CH:50][S:51][C:47]=3[CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:44]2[CH2:45][CH2:46][C:47]3[S:51][CH:50]=[CH:49][C:48]=3[CH:43]2[C:40]2[CH:39]=[CH:38][C:37]([O:36][C:35]([F:34])([F:53])[F:52])=[CH:42][CH:41]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: FC(F)(F)Oc1ccc(C2NCCc3sccc32)cc1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCc3sccc3C2c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117 %

Procedure:
4-Methoxybenzoic acid (0.64 g, 4.2 mmol) was dissolved in N,N-dimethylformamide (25 ml) and 1-hydroxybenzotriazole (0.71 g, 5 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol). The resulting mixture was stirred at room temperature for 30 minutes. 4-(4-Trifluoromethoxyphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.5 g, 5 mmol) followed by N,N-diisopropylethylamine (1.4 ml, 8.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (10 ml) was added and the mixture was extracted with diethyl ether (3×20 ml). The combined organic extracts were washed with saturated aqueous ammonium chloride (20 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluting with a mixture of ethyl acetate and heptane (1:2). The pure fractions were pooled and concentrated in vacuo. The residue was crystallised from a mixture of methyl tert-butyl ether and heptane to afford 2.13 g (98%) of the title compound.
Reaction SMILES: B.[C:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([NH:10][CH2:11]OC)=[O:9])#[N:3].[O:17]1[CH2:21]CC[CH2:18]1>>[NH2:3][CH2:2][CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([NH:10][CH2:11][CH2:18][O:17][CH3:21])=[O:9]
Reactant: COCNC(=O)c1cccc(CC#N)c1
Reactant: C1CCOC1
Agent: B
Product: COCCNC(=O)c1cccc(CCN)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Borane (1N in tetrahydrofuran, 467 ml, 0.467 mol) was added dropwise to a solution of 3-(cyanomethyl)-N-(methoxymethyl)benzamide (14.57 g, 0.067 mol) [see preparation 40] in tetrahydrofuran (30 ml) over 20 minutes. The reaction mixture was then stirred at room temperature for 18 hrs and then heated to reflux for 2 hrs, after which time the solvent was evaporated under reduced pressure and the residue acidified with hydrochloric acid (2N). The resultant mixture was heated to reflux for 10 minutes after which time it was basified with sodium hydroxide. The product was extracted with dichloromethane (3×30 ml), the combined organic layers were dried over MgSO4 and the solvent evaporated under reduced pressure. The crude product 20 was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5) changing to (92.5:7.5:0.25) changing to (90:10:1) to afford the title compound, 6.15 g, (44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11](Br)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH3:16])=[C:11]([C:23]3[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: COc1c(Br)cnn(-c2ccc(F)cc2)c1=O
Product: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 6 starting with 2-(4-fluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 70 mg, 61%). 1H NMR (500 MHz, DMSO-d6) δ 2.54 (s, 3H), 4.02 (s, 3H), 7.35 (dd, J=9.0, 9.0 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 7.65 (dd, J=9.0, 5.0 Hz, 2H), 8.14 (s, 1H). MS (APCI+) m/z 343 (M+H)+.
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[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[O:37]([NH2:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[CH3:38][O:37][NH:39][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: O=C(O)CCCCCCC(=O)c1ccc2ccccc2c1
Reactant: CON
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CONC(=O)CCCCCCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 7-(2-naphthoyl)heptanoic acid 50 g (500 mg, 1.76 mmol) in DMF (10 mL) were added HOBT (309 mg, 2.29 mmol) and EDC (504 mg, 2.64 mmol). The mixture was stirred at room temperature for 1 hour, after which methoxylamine-HCl (176 mg, 2.11 mmol) and triethylamine (300 μL, 2.11 mmol) were added and the solution was stirred at room temperature for 16 hours, then at 45° C. for 2 hours. The DMF was evaporated under high vacuum, deionized water was added, and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated sodium bicarbonate (10 mL), washed with brine (10 mL), and dried (MgSO4). The solvents were removed in vacuo and the title compound 64 (308 mg, 56%) was isolated by recrystallization from acetone. 1H NMR (400 MHz, 5:1 CDCl3:CD3OD): 8.37 (s, 1H), 7.89 (m, 2H), 7.78 (m, 2H), 7.48 (m, 2H), 3.59 (s, 3H), 3.01 (t, J=7.3 Hz, 2H), 1.96 (t, J=7.3 Hz, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.31 (m, 4H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].Cl>O1CCCC1.O>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:19])=[O:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (1.11 g) in tetrahydrofuran (40 mL) was added ethyl diethylphosphonoacetate (6.29 mL) dropwise under ice cooling. After stirring the mixture under ice cooling for 30 minutes, a solution of 2-nitrobenzaldehyde (3.0 g) in tetrahydrofuran (30 mL) was added thereto under ice cooling. The solution was stirred at room temperature for 8 hours. Water and 3N hydrochloric acid were then added to the solution and it was extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=3:2) to give the title compound (3.74 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:12][CH2:13][CH2:14][CH2:15][SH:16].[OH-].[K+]>COCCOC>[Cl:12][CH2:13][CH2:14][CH2:15][S:16][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: SCCCCl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Product: Nc1cc([N+](=O)[O-])ccc1SCCCCl
Yield: 16.5 %

Procedure:
2-Amino-4-nitro-fluorbenzene (500 mg, 3.2 mmol), 3-chloro-1 propanethiol (354 mg, 3.2 mmol), and potassium hydroxide (269 mg, 4.8 mmol) were mixed together in ethylene glycol dimethyl ether (6.4 mL) and heated at reflux for 72 hours. The reaction was filtered and the filtercake washed with chloroform. The filtrate was concentrated and purified by flash column chromatography on 10 g if silica gel and eluted with 3% methanol in chloroform to give 2-[(3-chloropropyl)sulfanyl]-5-nitrophenylamine (130 mg, 17%). 1H NMR (CDCl3, 300 MHz): δ7.49-7.48 (m, 2H), 7.38 (dd, 1H, J=7.7 Hz, J=7.7 Hz), 4.55 (s-broad, 2H), 3.64 (t, 2H, J=6.2 Hz), 3.03 (t, 2H, J=7 Hz), 2.00 (q, 2H, J=7 Hz) ppm. Mass Spec (ESI):264 (base M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]([O:20]C)=O)[CH:12]=1.C[O-].[Na+]>CO>[OH:3][NH:2][C:18](=[O:20])[CH2:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1
Reactant: NO
Reactant: COC(=O)Cc1cccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Cc1cccnc1)NO
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 13.8 g. (200 mmole) of hydroxylamine hydrochloride and 27.8 ml. (200 mmole) of triethylamine in 500 ml. of methyl alcohol was cooled to a temperature of -5° C. and 30.2 g. (200 mmole) of methyl 3-pyridineacetate were added. The mixture was stirred for 6 hours at room temperature and then 10.8 g. (200 mmole) of sodium methylate were added causing a slight exotherm to occur. The reaction mixture was then stirred for 27.5 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The crude residue of product was sonicated with 50 ml. of chloroform and filtered. The insoluble crude product (25.10 g) was crystallized from 50 ml. of water. There were obtained 15.54 g. of product melting with decomposition at about 163° C. to about 165° C.