Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]2[C:16](=[CH:17][C:18]([C:32]#[N:33])=[CH:19][CH:20]=2)[C:15]=1[Br:34])[CH2:9][CH:10]=C(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.C[OH:39]>>[C:1]([O:5][C:6]([N:8]([C:14]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]2[C:16](=[CH:17][C:18]([C:32]#[N:33])=[CH:19][CH:20]=2)[C:15]=1[Br:34])[CH2:9][CH:10]=[O:39])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Reactant: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC=O)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
A solution of 17 (180 mg, 0.345 mmol) in 22 mL (0.016 M) of 20% CH3OH--CH2Cl2 was cooled to -78° C. A stream of 3% O3 /O2 (160 L/min) was bubbled through the solution for 72 s. The reaction was immediately quenched with the addition of 0.81 mL of dimethyl sulfide and the mixture was allowed to stir at -78° C. for 5 min before being allowed to warm to 25° C. and stirred for 5 h. The solvent was removed in vacuo. Chromatography (SiO2, 2×20 cm, 30% EtOAc-hexane) afforded 18 (155 mg, 171 mg theoretical, 91%) as a white foamy solid: 1H NMR (CDCl3, 400 MHz) δ9.76 and 9.73 (two s), 8.63 and 8.61 (two s, 1H), 8.41 and 8.36 (two d, 1H, J=8.7 Hz), 7.64 and 7.60 (two dd, 1H, J=1.4, 8.7 Hz), 7.50-7.34 (m, 5H), 7.17 and 7.14 (two s, 1H), 5.26, 5.29 and 5.17 (one s and two d, 2H, J=11.4 Hz), 4.76 and 4.65 (two d, 1H, J=18.8 Hz), 4.01 and 3.95 (two d, 1H, J=18.8 Hz), 1.31 and 1.52 (two s, 9H); 13C NMR (CDCl3, 100 MHz, major rotamer) δ197.3, 154.1, 140.8, 135.6, 133.4, 132.0, 128.8, 128.7, 128.5, 127.9, 127.6, 127.1, 124.2, 118.7, 113.8, 112.0, 110.5, 81.8, 70.9, 58.9, 28.1; IR (film) vmax 2976, 2229, 1706, 1596, 1415, 1369, 1335, 1259, 1225, 1152, 1096, 848 cm-1 ; FABHRMS (NBA) m/z 495.0922 (M+ +H, C25H23BrN2O4 requires 495.0919).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26][CH:25]=[C:24]([CH3:27])[CH2:23][CH2:22][CH:21]=[C:20]([CH3:28])[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: ClCCl
Solvent: CSC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note all temperatures indicated are for the contents of the reaction flask) To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [BH4-].[Na+].[C:3]([CH:7]1[C:13](=[O:14])[CH2:12][CH:11]2[O:15][CH:8]1[CH2:9][CH2:10]2)([O:5][CH3:6])=[O:4]>CO>[C:3]([CH:7]1[CH:13]([OH:14])[CH2:12][CH:11]2[O:15][CH:8]1[CH2:9][CH2:10]2)([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C1C(=O)CC2CCC1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(O)CC2CCC1O2
Reaction time: 8 h

Procedure:
NaBH4 (2.56 g, 67.7 mmol) was added to a solution of 2-carbomethoxy-8-oxabicyclo(3.2.1)octan-3-one, 3, (5.12 g, 27.8 mmol) in MeOH (100 mL) at −78° C. The reaction mixture was left at room temperature overnight. The solution was concentrated to dryness. The residue was dissolved in water (50 mL), and extracted with CH2Cl2 (100, 2×50 mL). The combined dried (MgSO4) extracts were concentrated to dryness (yield: 3.9 g). By repeated flash column chromatography four isomers were obtained from the residue (2.9 g). The major isomer was 2α-carbomethoxy-3α-hydroxy-8-oxabicyclo(3.2.1)octane (1.0 g, 26%). Some of the other isomers were isolated to be used in the following reactions but there were still mixed fractions. Other pure isomers obtained:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:4]([C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])[CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)c(Br)c1
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: [K+]
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1ccc(Cl)c(-c2ccc(Cl)cc2)c1
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
3-Bromo-4-chloro-N-methoxy-N-methylbenzamide (1.0 mg, 3.8 mmol, 1.0 eq) and 4-chloro phenyl boronic acid (787 mg, 5 mmol, 1.3 eq) was dissolved in toluene and stirred for 10 minutes. The solution was purged with nitrogen for 10 minutes and degassed under vacuum. Tetrakis triphenylphosphinepalladium (223 mg, 0.19 mmol, 0.05 eq) and K2CO3 (696 mg, 5 mmol, 1.3 eq) were added to the reaction. The mixture was refluxed for 12 h under nitrogen and the volatiles were removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (60-120) eluting with 5-10% ethyl acetate/hexane to afford the desired compound (1 g, 90%). 1H NMR (400 MHz, CD3OD) δ 3.37-3.39 (s, 3H), 3.60-3.64 (s, 3H), 7.10-7.13 (t, 1H), 7.25-7.27 (t, 1H), 7.43-7.48 (m, 3H), 7.60-7.63 (m, 3H). MS (ESI): 310.2 (M+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:17]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCn1ccc2cc(C(=O)O)ccc21
Reaction time: 12 h

Procedure:
Sodium hydride (50% in oil, 1.4 g) was added to methyl 1H-indole-5-carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution ceased, bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml) and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (C13H15NO2); MS (ESI): 218 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCC(C(=O)c2ccc(C(C)(C)C)cc2)CC1

Procedure:
19.1 g of 1-acetylisonipecotoyl chloride, Example 1(b) are added portionwise to a stirring suspension of 13 g of t-butylbenzene and 27 g of aluminum chloride in 175 ml of dichloroethane. The reaction mixture is refluxed for 1 hours, cooled, and poured onto ice. The organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined, dried, and the solvent is removed under reduced pressure leaving the oil, 1-acetyl-4-(4-t-butylbenzoyl)piperidine.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[C:6]=1[Cl:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1n[nH]c(C(C)(C)C)c1Cl

Procedure:
5.8 g (0.03 mole) of 5-t-butyl-3-propionylaminopyrazole prepared in Example 5 was dispersed in 30 ml of chloroform, and the dispersion was stirred while adding dropwise thereto sulfuryl chloride. The mixture was further heated under reflux conditions for one hour, and the solvent was distilled off. To the residue was added a sodium bicarbonate aqueous solution whereby crystals were precipitated. The crystals were collected by filtration, washed with water and then dried to obtain 3.9 g of 5-t-butyl-4-chloro-3-propionylaminopyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 136° to 137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)[OH:16]>>[F:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[F:1])[NH:9][C:10](=[O:14])[C:11]2=[O:16]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(F)c(F)c1
Product: O=C1Nc2cc(F)c(F)cc2C1=O

Procedure:
In accordance with the above reaction scheme, an aqueous solution of 3,4-difluoroaniline (I) and hydroxylamine hydrochloride containing hydrochloric acid is reacted with an aqueous solution of chloral hydrate and sodium sulfate at the reflux, then filtered while hot, giving N-(3,4-difluorophenyl)-2-(hydroxyimino)-acetamide (II). The compound (II) is reacted with concentrated sulfuric acid with heat, then added to cracked ice, giving 5,6-difluoro-1H-indole-2,3-dione (III). A basic aqueous solution of compound (III) is treated with hydrogen peroxide and heat, then cooled and acidified, giving 2-amino-4,5-difluorobenzoic acid (IV). The compound (IV) is added to a mixture of anhydrous copper(II) chloride, t-butyl nitrite and anhydrous acetonitrile at 0°-5° C., then added to a dilute mineral acid, giving 2-chloro-4,5-difluorobenzoic acid (V).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>>[OH:1][CH:2]([CH2:15][NH:20][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])[CH2:3][O:4]/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]\1=2
Reactant: c1cc2c(s1)CCC/C2=N\OCC1CO1
Reactant: CN(C)CCN
Product: CN(C)CCNCC(O)CO/N=C1\CCCc2sccc21
Yield: 28 %

Procedure:
This compound is prepared by the procedure described in Example 1 by condensing E-4-(2,3-epoxypropoxy)imino-4,5,6,7-tetrahydrobenzo[b]thiophene with β-dimethylaminoethylamine. Dioxalate: white crystals; m.p. 222° C. (recrystallised from methanol/water); yield: 28% of theory.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(OCC)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][O:31][C:35](=[O:37])[CH3:36])=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CO)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxymethylphenyl)benzamide (100 mg) and acetic anhydride (34 mg) in pyridine (5 ml) was stirred at ambient temperature for 3 days and the solvent was evaporated in vacuo. The residue was dissolved in chloroform and the organic solution was washed successively with 1N hydrochloric acid, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-acetoxymethylphenyl)benzamide (105 mg) as a white powder.
Reaction SMILES: [Mg].[CH3:2][C:3]1[O:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH2:10](Br)[C:11]#[CH:12].C(OC(C)C)(C)C>[Cl-].[Zn+2].[Cl-].C(Br)C#C.O1CCCC1>[OH:8][CH:7]([C:6]1[O:9][C:3]([CH3:2])=[CH:4][CH:5]=1)[CH2:12][C:11]#[CH:10]
Reactant: Cc1ccc(C=O)o1
Reactant: C#CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C#CCC(O)c1ccc(C)o1
Temperature: 10 °C
Yield: 80.6 %

Procedure:
In the same flask as in Example 1, there were charged granular magnesium (14.6 g), dry zinc chloride (6.8 g) and dry tetrahydrofuran (110 g). Propargyl bromide (0.88 g) was added thereto at 10° C. while stirring. The resultant mixture was kept in an adiabatic condition, whereupon the reaction proceeded. When the heat generation stopped, a mixture of 5-methylfurfural (55.06 g), propargyl bromide (64.5 g), tetrahydrofuran (55 g) and isopropyl ether (55 g) was dropwise added to the reaction mixture at 50° C. in 1.5 hours while stirring under cooling. The resultant mixture was kept at room temperature for 30 minutes while stirring. After completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 to give 2-(1-hydroxy-3-butynyl)-5-methylfuran (60.5 g) in a yield of 81% (based on the starting 5-methylfurfural).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]([NH2:36])[CH3:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][C@H:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[CH3:35]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccc(F)cc1
Yield: 58.2 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (7.0 g, 16.4 mmol) with (S)-1-(4-fluorophenyl)ethylamine (6.9 g, 49.3 mmol) in toluene (175 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give 7-chloro-6-[1-(S)-(4-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.96 g, 58%). GC-MS m/z: 414 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:21][CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)=[N:29][CH:30]=1>>[C:1]([C:3]1[CH:4]=[C:5]([S:21][CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:38][CH2:37][CH:34]4[CH2:35][CH2:36][N:31]([C:28]5[CH:27]=[CH:26][C:25]([C:24]([F:40])([F:39])[F:23])=[CH:30][N:29]=5)[CH2:32][CH2:33]4)=[O:17])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: NCC1CCN(c2ccc(C(F)(F)F)cn2)CC1
Reactant: CSc1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CSc1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)oc12

Procedure:
The title compound was prepared from 4-[5-cyano-7-(methylthio)-1,3-benzoxazol-2-yl]benzoic acid and 1-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methanamine (INTERMEDIATE 5) by a procedure analogous to that described in EXAMPLE 35. Mass spectrum (ESI) 552.0 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.38 (s, 1H), 8.35 (d, J=8.3 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H), 7.89 (s, 1H), 7.60 (dd, J=2.3 Hz, J=9.2 Hz, 1H), 7.45 (s, 1H), 6.65 (d, J=9.1 Hz, 1H), 6.32 (t, J=5.9 Hz, 1H), 4.46 (d, J=13.3 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.94 (m, 2H), 2.70 (s, 3H), 1.99 (m, 1H), 1.90 (br d, J=11.6 Hz, 2H), 1.34 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[N:8][CH:9]=[C:4]2[C:3]([C:10]2[O:19][C:13]3=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]3[CH:11]=2)=[CH:2]1.[I:20]N1C(=O)CCC1=O>CN(C)C=O>[I:20][C:17]1[CH:16]=[N:15][C:14]([NH2:18])=[C:13]2[O:19][C:10]([C:3]3[C:4]4[C:5](=[CH:6][N:7]=[N:8][CH:9]=4)[S:1][CH:2]=3)=[CH:11][C:12]=12
Reactant: Nc1nccc2cc(-c3csc4cnncc34)oc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3csc4cnncc34)oc12
Yield: 88.3 %

Procedure:
A solution of 2-(thieno[2,3-d]pyridazin-3-yl)furo[2,3-c]pyridin-7-amine (30.0 mg, 0.112 mmol) and N-iodosuccinimide (101.6 mg, 0.4516 mmol) in N,N-dimethylformamide (2 mL) was stirred at 40° C. for 45 min. The reaction was removed from the heat and 1.0 M aqueous sodium thiosulfate solution (2 mL) was added. The crude mixture was concentrated in vacuo. The residue was then suspended in water and the fine solid was filtered off and dried, giving 39.0 mg (88%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 10.48 (d, J=1.52 Hz, 1H), 10.02 (d, J=1.52 Hz, 1H), 9.04 (s, 1H), 7.96 (s, 1H), 7.45 (s, 1H), 6.89 (s, 2H); MS (ESI): 395.07 [M+H]+; HPLC: tR=2.83 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[CH2:20]([NH2:22])[CH3:21]>CN1CCCC1=O.O>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[NH:22][CH2:20][CH3:21]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Reactant: CCN
Solvent: CN1CCCC1=O
Solvent: O
Product: CCNc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 150 °C
Yield: 60 %

Procedure:
A mixture of 4-chloro-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-pyridine (1.330 g, 4.822 mmol) and 20 ml of ethyl amine in 13 ml of 1-methyl-2-pyrrolidinone was heated at 150° C. at 250 psi overnight in a pressure reactor. The reaction was heated an additional 24 hours at 175° C. and 300 psi. The reaction mixture cooled to room temperature and diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using chloroform to 2% methanol in chloroform as eluent to give 0.820 g (60%) of the title compound as a white solid, mp 115–116° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[CH2:16](I)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:16][CH3:17])=[O:8]
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
A suspension of 2-methyl-5-phenyl-3-furancarboxylic acid (5.0 g), ethyl iodide (4.7 g) and potassium carbonate (3.5 g) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.7 g, 100%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2Cl)[CH:6]=1)=[O:4].[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:1][N:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[NH:33][C:29]2[CH:30]=[C:31]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:23])=[CH:32]3)[CH:6]=1)=[O:4]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN(CCN1CCOCC1)C(=O)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N(C)CCN5CCOCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid methyl-(2-morpholin-4-yl-ethyl)-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 450 (MH+), HPLC Rf: 3.58 min.; HPLC purity: 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Br>>[CH3:16][O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CCCBr
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COC(=O)CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 52.5 %

Procedure:
The title compound (1.56 g, 52.6%) was synthesized from 1-(4-nitro-phenyl)-piperazine (2 g, 9.66 mmol) and 4-bromo-butyric acid methyl ester (1.75 g, 9.83 mmol) by the procedure described in step 1 of Example 1 MS (ESI) m/z 264 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.86 (m, 2H), 2.39 (m, 4H), 2.58 (t, J=5.2 Hz, 4H), 3.41 (t, J=5.2, 4H), 3.68 (s, 3H), 6.81 (m, 2H), 8.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:10]#[N:11].Cl.Cl[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.[OH-].[Na+]>CS(C)=O>[C:10]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([CH2:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)#[N:11]
Reactant: ClCn1cncn1
Reactant: N#CC(CCCN1CCCCC1)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC(CCCN1CCCCC1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
This compound (5.0 g.) was prepared using the procedure described in Example 9b except using 5.0 g. (0.016 mole) of 2-(2,4-dichlorophenyl)-5-(1-piperidinyl)valeronitrile, 2.7 g. (0.0176 mole) of 1-(chloromethyl)-1,2,4-triazole hydrochloride, 3.2 g. (0.040 mole) of aqueous 50% sodium hydroxide, and 50 ml. of DMSO and was isolated as an oil.