Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (CAS number 71701-92-3; 2.86 g, 10.98 mmol), DIPEA (1.74 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol), then by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:21][N:22]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.NO>CN(C)C=O.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([NH:22][OH:21])=[O:20])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)NO)cc1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To N-{[4-(2-butynyloxy)phenyl]sulfonyl}-beta-alanine (0.80 g, 2.69 mmol) in dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.436 g, 3.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.67 g, 3.5 mmol). After one hour 50% hydroxylamine in water (1.3 mL) was added. The reaction mixture was stirred overnight and concentrated in vacuo. Ethyl acetate was added and the organic phase washed with water (2×) and brine then dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave a white solid that was triturated with ethyl acetate to give 3-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxypropanamide (0.30 g) as a white solid,. mp 118-128° C. Electrospray Mass Spec 313.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:29])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@@H:17]([NH:20]C(=O)OC(C)(C)C)[C@@H:16]([OH:28])[CH2:15]2)=[N:4][CH:3]=1.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:29])[CH2:15][C@@H:16]1[OH:28]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@@H]1O
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl {(3S,4R)-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-3-hydroxy-4-piperidinyl}carbamate (310 mg, 0.7627 mmol) was dissolved in DCM (1 ml) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (1 ml). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give 1-{2-[(3S,4R)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride as an off-white solid (253 mg).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:24])=[CH:26][CH:27]=2)[C:8]2[S:16][C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2ccncc12
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccncc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a mixture of 4-{[cyclohexyl(3-methylthieno[3,2-c]pyridin-2-yl)methyl]amino}benzoic acid (209 mg) synthesized in Example A138(4), ethyl 3-(methylamino)propanoate (108 mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (229 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg), and the mixture was stirred overnight at room temperature. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane, then 0-10% methanol/ethyl acetate) to give the title object compound (180 mg, 66%) as a colorless oil.
Reaction SMILES: [CH:1](/[CH:6]([CH2:9][OH:10])[CH2:7][OH:8])=[CH:2]\[CH2:3][CH2:4][CH3:5].[CH2:11]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14].C1(C)C=CC=CC=1>S(=O)(=O)(O)O.C(N(CC)CC)C.O>[CH2:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:20]2[O:10][CH2:9][C@H:6](/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)=[CH:22][CH:23]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCC/C=C/C(CO)CO
Reactant: CCCCOc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC/C=C/[C@H]1CO[C@H](c2ccc(OCCCC)cc2)OC1

Procedure:
A mixture of 1.00 g of 2-(trans-1-pentenyl)-1,3-propanediol, 1.11 g of p-butoxybenzaldehyde, 3 drops of 2N sulphuric acid and 40 ml of toluene was heated to reflux for 2 hours with separation of water. The mixture was subsequently treated with 7 drops of triethylamine, left to cool, washed with 5 ml of saturated sodium hydrogen carbonate solution and three times with 10 ml of water each time, dried over sodium carbonate, filtered and concentrated. The semi-crystalline residue (1.86 g) was chromatographed on silica gel with hexane/diethyl ether (vol. 97:3). The product-containing fractions were pooled (0.99 g) and recrystallized twice from hexane at -25° C. There was obtained 0.44 g of pure trans-2-(p-butoxyphenyl)-5-(trans-1-pentenyl)-m-dioxane; m.p. (C-N) 60.6° C., cl.p. (N-I) 61.9° C.
Reaction SMILES: [CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC(C1CCCCC1)C1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CC(C1CCCCC1)C1CCCCC1
Reaction time: 1 h
Yield: 98 %

Procedure:
A stirred solution of 3,3-dicyclohexylpropionic acid (15.2 g, 0.064 mol) in 225 ml of dichloromethane was cooled to 5° C. and treated with 6.8 ml (0.078 mol) of oxalyl chloride, followed by 10 drops of dimethylformamide. The cooling bath was removed and stirring was continued at room temperature. Gas evolution, which was vigorous initially, essentially ceased after 1 hour. After 3 hours, dichloromethane and excess oxalyl chloride were removed on a rotary evaporator. The residue was taken up in dichloromethane and the evaporation was repeated to give 16.1 g of a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[K]>C1(C)C=CC=CC=1>[CH2:17]([O:24][C:25]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH2:1])[CH2:4][CH2:5]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCNCC1
Agent: [K]
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 91 %

Procedure:
22.2 g(0.2 mol) of 4-aminomethyl-piperidine was dissolved in 250 ml of toluene and then 21.2 g(0.2 mol) of benzaldehyde was added thereto. The mixture was refluxed for 3 hours with Dean-stack and cooled down to 0° C., and then 34.2 g(0.2 mol) of benzylchloroformate was added thereto while stirring. After the mixture was stirred for 3 hours, 1N aqueous potassium hydrosulfate solution(220 ml) was added thereto at room temperature. The mixture was extracted three times with 200 ml of diethylether, and then the aqueous layer was basified with sodium hydroxide. The aqueous solution was saturated with sodium chloride and extracted three times with 100 ml of dichloromethane. The organic solution was dried over magnesium sulfate and distilled under reduced pressure to obtain 38 g(Yield 91%, Molecular weight 248) of the title compound
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C([Mg]Br)=C.C([Mg]Cl)#C.C([Mg]Br)#C.C=CC[C@H](O)CCCCCC.C#CC[C@H](O)CCCCCC.[CH2:39]([C@@H:42]([CH2:46][CH2:47][CH2:48][CH2:49]CC)[C:43]([OH:45])=[O:44])[CH:40]=[CH2:41].C([C@@H](CCCCCC)C(O)=O)C#C>>[CH2:39]([C@H:42]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:1][CH3:2])[C:43]([OH:45])=[O:44])[CH2:40][CH3:41]
Reactant: C=C[Mg]Cl
Reactant: C=CC[C@@H](CCCCCC)C(=O)O
Agent: C#CC[C@@H](CCCCCC)C(=O)O
Agent: C#CC[C@H](O)CCCCCC
Agent: C#C[Mg]Br
Product: CCCCCC[C@@H](CCC)C(=O)O

Procedure:
Additionally, it is also possible in the above reaction steps that, for example, in the step (A), a two-carbon adding reaction is carried out using an unsaturated organic metal reagent (e.g., vinyl magnesium chloride, vinyl magnesium bromide, ethynyl magnesium chloride, ethynyl magnesium bromide, etc.) as an organic metal reagent, the resulting (4R)-1-decen-4-ol or (4R)-1-decyn-4-ol is subjected to the reactions of the step (B) or the step (C), and the resulting (2R)-(2-propenyl)octanoic acid or (2R)-(2-propynyl)octanoic acid is reduced by the method mentioned in WO 99/58513 and WO 00/48982 to give (2R)-2-propyloctanoic acid of high purity.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:19]3[C:18]([CH2:20][O:21]C)=[N:17][N:16]([CH:23]4[CH2:25][CH2:24]4)[C:15]=3[C:14](=[O:26])[N:13]2[C:27]2[CH:28]=[C:29]([CH3:37])[C:30]3[N:31]([C:33]([CH3:36])=[N:34][N:35]=3)[CH:32]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:19]3[C:18]([CH2:20][OH:21])=[N:17][N:16]([CH:23]4[CH2:24][CH2:25]4)[C:15]=3[C:14](=[O:26])[N:13]2[C:27]2[CH:28]=[C:29]([CH3:37])[C:30]3[N:31]([C:33]([CH3:36])=[N:34][N:35]=3)[CH:32]=2)=[CH:10][CH:11]=1
Reactant: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3c(c(CO)nn3C3CC3)C2c2ccc(Cl)cc2)cn2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
BBr3 (1 M in CH2Cl2, 0.337 mL, 0.337 mmol) was added to a solution of 4-(4-chlorophenyl)-1-cyclopropyl-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (130 mg, 0.281 mmol) (Example 130) in CH2Cl2 (5 mL), under an argon atmosphere. The reaction mixture was stirred for 1 h at rt, quenched with brine (100 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried on Na2SO4 and the solvent was evaporated off under reduced pressure. After purification by silica gel column chromatography (CH2Cl2/MeOH 2-8%), the resulting residue was triturated in diethyl ether to provide the title compound (28 mg) as a colorless solid. tR: 0.77 min (LC-MS 2); ESI-MS: 449.1 [M+H]+ (LC-MS 2); Rf=0.29 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.09 (m, 2H) 1.19-1.28 (m, 2H) 2.42 (s, 3H) 2.61 (s, 3H) 3.80-3.90 (m, 1H) 4.06 (dd, J=12.90, 5.87 Hz, 1H) 4.30 (dd, J=12.90, 4.30 Hz, 1H) 5.10 (dd, J=5.87, 4.30 Hz, 1H) 6.46 (s, 1H) 7.26-7.41 (m, 5H) 8.49 (s, 1H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1
Reactant: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
3-[4-(Azidomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (225 mg, 0.66 mmol) was dissolved in anhydrous THF (5.6 mL) and water (5.6 mL). The reaction was cooled to 0° C. followed by addition of triphenylphosphine (192 mg, 0.73 mmol). The reaction was allowed to warm to rt and was stirred overnight. The reaction was stripped to dryness, azeotroped with toluene and redissolved in MeOH. The crude residue was purified by preparative LCMS to yield the desired product (200 mg, 96%). MF═C11H7ClFN5O3; LCMS calculated for C11H8ClFN5O3(M+H)+: m/z=312.030.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:17]=[CH:16][C:15]=3[S:28][C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(COc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (0.037 g, 0.205 mmol) was reacted with the product from Example 221d (0.066 g, 0.205 mmol) for 16.5 hours following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.041 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3 H) 5.13 (s, 2 H) 6.31 (d, J=6.99 Hz, 1 H) 6.79 (d, J=8.46 Hz, 2 H) 6.88-7.12 (m, 4 H) 7.20-7.36 (m, 4 H) 7.46-7.56 (m, 2 H) 7.81 (d, J=8.82 Hz, 1 H) 8.48 (d, J=6.99 Hz, 1 H) 9.02 (d, J=8.46 Hz, 1 H) 10.01 (s, 1H); MS (ESI+) m/z 466.3 (M+H)+; (ESI−) m/z 464.2 (M−H)−.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].CO.[CH2:7]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:9][CH3:10]>O1CCOCC1>[CH2:15]([N:14]1[CH2:13][CH2:12][N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][C:1]1=[O:2])[CH2:16][CH2:17][CH3:18]
Reactant: O=CC=O
Reactant: CCCCNCCNCCCC
Solvent: CO
Solvent: C1COCCO1
Product: CCCCN1CCN(CCCC)C(=O)C1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To 10 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of methanol is rapidly added 11.9 g (69.0 mmoles) of N,N'-di(n-butyl)ethylenediamine. The solution is rapidly brought to reflux and heating is maintained for 5 minutes. The dark brown solution is then allowed to cool to room temperature at which time fine white crystals precipitate from the brown oil. The oil is diluted with 100 ml of 1,4-dioxane and the solid is removed by filtration. The dioxane solution is concentrated under aspirator vacuum and distilled in a short path distillation apparatus to give 4.5 g of 1,4-di(n-butyl)piperazin-2-one in the form of a brown oil (31 percent yield).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](Cl)(Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9]2(=[O:10])[O:19][CH2:15][CH2:16][CH2:17][O:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCCO
Reactant: O=[N+]([O-])c1ccc(CP(=O)(Cl)Cl)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude (4-Nitrobenzyl)phosphonic dichloride (Compound 230E) above was dissolved in anhydrous THF (20 mL). To this solution was added TEA (840 mg, 7.5 mmol) and 1,3-propane-diol (190 mg, 2.5 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, concentrated and the residue was purified by column chromatography to give the target product (70 mg). 1H NMR (CD3OD, 400 MHz): δ=2.85 (d, J=20.0 Hz, 2H), 3.28-3.30 (m, 2H), 3.55-3.58 (m, 2H), 3.75-7.78 (m, 2H), 6.64 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: Nc1cccc2c1OCC2
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccc2c1OCC2

Procedure:
To a solution of 15 g. of 2,3-dihydro-7-benzofuranamine in 150 ml. of methanol is added 8.5 ml. of isopropyl iodide and 13.4 ml. of triethylamine. The solution is refluxed for 45 hours and then concentrated in vacuo. The resulting oil is extracted several times with diethyl ether, the ether extracted combined filtered through Celite, and the ether removed in vacuo to obtain an oil of N-isopropyl-2,3-dihydro-7-benzofuranamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.Cl.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH2:28])[CH2:27][O:26][CH2:25]1>>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1([NH:28][C:15]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]3([CH3:14])[CH2:11][O:12][CH2:13]3)[N:6]=2)=[O:17])[CH2:27][O:26][CH2:25]1
Reactant: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Reactant: NC1(c2nccs2)COC1
Agent: Cl
Product: CC1(COc2nc(C(=O)NC3(c4nccs4)COC3)ccc2Br)COC1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=440.4 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)(=[O:9])=[O:8].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:29])([F:28])[F:17])=[CH:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(NCCCCO)c1cccc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
Using a method analogous to that described in Example 40, 3-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-trifluoromethylphenyl boronic acid were reacted to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=[CH:4][C:3]=1[C:22]#[N:23].Cl.N1C=CC=CC=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])#[CH:32].C(OC(O)C)C.C(=O)([O-])[O-].[K+].[K+]>O>[C:31]([C:33]1[CH:34]=[C:35]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=3[O:12][CH2:13][CH2:14][O:15][CH3:16])[N:5]=[CH:4][C:3]=2[C:22]#[N:23])[CH:37]=[CH:38][CH:39]=1)#[CH:32]
Reactant: COCCOc1ccc2ncc(C#N)c(Cl)c2c1OCCOC
Reactant: C#Cc1cccc(N)c1
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(OCCOC)c(OCCOC)c23)c1

Procedure:
A stirred mixture of 4-Chloro-5,6-bis(2-methoxyethoxy)-3-quinolinecarbonitrile (2.52 g, 7.5 mmol), pyridine hydrochloride (0.87 g, 9.0 mmol), 3-ethynylaniline (1.06 g, 9.0 mmol), and ethoxyethanol (22 ml) was refluxed for 1.5 h, cooled, diluted with water containing potassium carbonate to give pH˜9, and extracted with ethyl acetate. The extract was washed well with water, dried, and concentrated. The resulting solid was recrystallized from ethyl acetate to give an off-white solid, mp 150-153°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH+:7]([O-:36])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1cccnc1)c1ccc(OCC2CC2)c2oc3ccccc3c12
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCC2CC2)c2oc3ccccc3c12)[NH+]([O-])c1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A suspension of N-(pyrid-3-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide (15 mg, 0.139 mmol) (example 30) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.698 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. The reaction contents were washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 40% acetone-chloroform as the eluent to give 30 mg of N-(pyrid-3-yl)-4-cyclopropylmethoxy-dibenzo[b,d]furan-1-carboxamide-N-oxide as white solid; mp: 272-275° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]2=[O:32])=[CH:5][C:3]=1[NH2:4].C(O[C:36]1[CH2:40][C:39](=[O:41])[N:38]([C:42]2[C:47]([Cl:48])=[CH:46][C:45]([Cl:49])=[CH:44][C:43]=2[Cl:50])[N:37]=1)C.CS(O)(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]2=[O:32])=[CH:5][C:3]=1[NH:4][C:36]1[CH2:40][C:39](=[O:41])[N:38]([C:42]2[C:47]([Cl:48])=[CH:46][C:45]([Cl:49])=[CH:44][C:43]=2[Cl:50])[N:37]=1
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: CCCCCCCCCCCCCCCCCCN1CCN(c2ccc(Cl)c(N)c2)C1=O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCN1CCN(c2ccc(Cl)c(NC3=NN(c4c(Cl)cc(Cl)cc4Cl)C(=O)C3)c2)C1=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 13.9 g of 2-chloro-5-(3-octadecylimidazolidin-2-on-1-yl)aniline, 9.3 g of 3-ethoxy-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 1 g of methanesulfonic acid was heated at 150° C. under reduced pressure with stirring for 6 hours. After cooling, the reaction mixture was dissolved in ethyl acetate and washed three times with water. After distilling off the solvent, the residue was separated by a silica gel chromatography (using a solvent mixture of ethyl acetate and benzene as a spreading agent) to obtain the desired compound. By recrystallization from a solvent mixture of ethyl acetate and acetonitrile 10.5 g of the crystals having a melting point of 163° to 168° C. were obtained.