Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Br:13]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:13][C:10]1[C:4]2=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]([Cl:1])=[C:3]2[S:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2c(Br)csc2c1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.1 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (100 mg, 0.51 mmol) and N-bromosuccinimide (118 mg, 0.66 mmol) in 0.63 mL of dimethylformamide is stirred at room temperature for 4 days. Additional N-bromosuccinimide (118 mgs) is added and the reaction mixture is heated at 40° C. for 17 hours. Additional N-bromosuccinimide (118 mgs) is added and the reaction mixture is heated at 40° C. for 24 hours. Additional N-bromosuccinimide (118 mgs) is added and the reaction mixture is heated at 60° C. for 24 hours. The mixture is cooled to room temperature and treated with ice water and neutralized with aqueous saturated sodium bicarbonate. The resultant solid is purified by flash column chromatography eluting with 10% hexane in dichloromethane to provide 35 mg of 3-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 176–178° C.; 1H NMR (DMSO-d6) δ 8.79 (s, 1H), 9.23 (s, 1H); MS 272.9, 274.8.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>CN(C)C=O.C(OCC)(=O)C>[N+:20]([C:9]1[CH:10]=[CH:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)[CH:7]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine (191 mg) in N,N-dimethylformamide (10 mL), and 3-(trifluoromethyl)benzylamine (210 mg). The resulting solution was stirred overnight at 50° C. The resulting mixture was dissolved in 50 mL of ethyl acetate and washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography to give 186 mg of product as yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([Cl:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C)c(Cl)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (4.54 g) in DMF (34.0 mL) was added N-chlorosuccinimide (2.47 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.20 g).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])=O.[CH:26]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])OCC>C(O)C>[CH2:34]([O:33][CH:26]([O:30][CH2:31][CH3:32])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:23])([F:25])[F:24])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])[CH3:35]
Reactant: COc1c(C=O)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC(OCC)c1cc(C(=O)N2CSc3ccccc32)cc(C(F)(F)F)c1OC

Procedure:
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole (277 mg) was dissolved in ethanol (1.5 mL) and triethyl orthoformate (0.16 mL), Amberlyst-15 (27 mg) was added to the solution, and then the mixture was refluxed for 3.5 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (326 mg) as a yellow oily substance.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]2[C:6]1=[O:11])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)CN
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 3.2 cm3 of isobutylamine in 3 cm3 of toluene is added to a suspension of 5.2 g of phthalic anhydride in 50 cm3 of toluene, with stirring. The reaction mixture is heated at a temperature in the region of 60° C. for 1 hour, and then at a temperature in the region of 100° C. for 2 hours. Dean-Stark apparatus is then installed on the reactor and the reaction mixture is heated at a temperature in the region of 130° C. for 2 hours, after which it is cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 50 cm3 of saturated sodium bicarbonate solution and extracted twice with 75 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. 6.5 g of N-isobutylphthalimide are thus obtained in the form of a white solid melting at 92° C.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]([CH2:29][CH3:30])[C:19]=4[N:20]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([OH:28])=[O:27])=[CH:22][N:21]([CH2:29][CH3:30])[C:19]=4[N:20]=3)[CH2:11][CH2:10]2)=[CH:31][CH:32]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc(N)cc4)CC3)nc21

Procedure:
A solution of 3.40 g of 2-[4-(p-nitrobenzyl)-1-piperazinyl]-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 200 ml of acetic acid was hydrogenated over 0.55 g of 5% palladium-on-charcoal catalyst at room temperature until 3 mole equivalents of hydrogen were absorbed. The catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure. To the residue was added 30 ml of water and the resulting solution was neutralized with a saturated sodium bicarbonate solution. The crystalline precipitate was collected by filtration and dissolved with warming in 100 ml of ethanol. After removal of the insoluble material by filtration, the filtrate was kept under cooling to give the crude precipitated product (1.80 g), which was dissolved in a minimum amount of chloroform and chromatographed on 14 g of silica gel, using chloroform-methanol (a 50:1 ratio by volume) as eluent. Fractions containing the desired product were pooled and concentrated to dryness. The resulting solid was recrystallized from ethanol to give the pure product, m.p. 198°-201° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14]C)=O)=[O:8])[CH3:2].CC([O-])(C)C.[K+].O.Cl>C1COCC1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][C:7](=[O:8])[NH:9][C:10]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=2[C:12]1=[O:14])=[O:21])[CH3:2]
Reactant: CCOC(=O)CCC(=O)Nc1ccc(I)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=O)Nc2ccc(I)cc2C1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-(4-ethoxy-4-oxobutanamido)-5-iodobenzoate (ii-a) (22.0 g, 54 mmol) in 125 mL of THF was added a 1 M solution of KOt-Bu in THF (119 mL, 119 mmol). The reaction was complete after 2.5 h at 22° C. H2O (250 mL) and 1N HCl (60 mL) were added to the solution, and the resulting precipitate was filtered, washed with 2×50 mL Et2O, and dried in vacuo to give iii-a (16.1 g, 83%) as a whitish/gray solid as a mixture of ethyl and methyl esters: MS m/z═374 (M+H) and 360 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[N:14][C:15]([CH3:25])=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: Cc1nc2c(cc1C#CCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2c(cc1CCCO)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1,7-dimethyl4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide (0.12 g, 0.30 mmol) in CH2Cl2 (20 mL) and MeOH (3 mL) is added 10% Pd/C (21 mg). The reaction is subjected to hydrogenation at 18 psi for 30 min. The reaction is filtered over Celite and monitored to determine the extent of the reaction. Fresh catalyst is added and the reaction is placed under hydrogen at 18 psi again. After another 30 minutes, the reaction is complete. The reaction is filtered over Celite. The filter cake is rinsed thoroughly with CH2Cl2, and MeOH. The filtrate is concentrated in vacuo and the residue is then dissolved in CH2Cl2 and adsorbed onto silica. Purification by chromatography (eluent 1% MeOH/CH2Cl2 (1 L), 2% MeOH/CH2Cl2 (1 L), 4% MeOH/CH2Cl2 (1 L)) affords the desired product as a white solid (0.079 g, 0.20 mmol, 66%). Physical characteristics are as follows: m.p. 176-177° C.; 1H NMR (300 MHz, DMSO-d6) δ10.30, 8.98, 8.35, 7.41, 7.36, 4.59, 4.56, 4.01, 3.47, 2.82, 2.67, 1.75; IR (drift) 1658, 1609, 1556, 1531, 1503, 1458, 1420, 1357, 1333, 1260, 1095, 1056, 1017, 811, 701 cm−1; MS (ESI) m/z 400.1 (M+H)+, 398.1 (M-H); HRMS (FAB) calcd for C21H22ClN3O3+H1 400.1428, found 400.1434.
Reaction SMILES: Br[CH2:2][CH2:3][C@@:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.CCOC(C)=O>[N:15]([CH2:2][CH2:3][C@@:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:16]=[N-:17]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@](C)(CCN=[N+]=[N-])S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a solution of ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate (4.5 g, 15.7 mmol, 1 eq) in DMSO (5 mL) was added sodium azide (1.02 g, 15.7 mmol, 1 eq). The mixture was heated at 80° C. for 3 h. The mixture was then diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to give ethyl (2R)-4-azido-2-methyl-2-(methylsulfonyl)butanoate which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[H-].[Na+].O>CN(C)C=O>[Cl:10][C:8]1[C:7]([F:11])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[N:9]=1
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Cl)nc1OCC(F)(F)F
Temperature: 120 °C
Yield: 75.8 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (900 mg, 5.7 mmol), 2,2,2-trifluoro-ethanol (570 mg, 5.7 mmol), and NaH (60%) (273 mg, 6.8 mmol) in N,N-dimethylformamide (15 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed to give the title compound (1100 mg, 76%). MS (DCI/NH3) m/z 255 (M)+, 257 (M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[C:19]=[O:20]>>[CH:21]1([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=NC1CCCCC1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCCCC1

Procedure:
Example 7 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and isocyanatocyclohexane (17.4 μl) to give the title compound (0.0298 g). LC-MS (System A): Rt 2.26 mins, Mass Spectrum m/z 400 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]O)[CH2:25][CH2:24]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH2:31][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(O)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Reactant: CN1CCN(CCCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(OCCCN2CCN(C)CC2)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
To a solution of 2-(3-chloro-4-fluoro-phenylamino)-N-(5-hydroxy-2-methyl-phenyl)-acetamide (0.400 g) and 4-methyl-1-piperazinepropanol (0.270 g) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added tributylphosphine (0.64 ml) and 1,1′-(azodicarbonyl)dipiperidine (0.656 g) and the mixture stirred at ambient temperature for 20 hours. The reaction mixture was poured into diethylether and filtered through Celite. After concentration, the residue was purified by NPHPLC (eluting with 75% ethanol in dichloromethane) to afford the title compound (0.334 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9](=[N:18][OH:19])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17].[CH:20]([S:23](Cl)(=[O:25])=[O:24])([CH3:22])[CH3:21]>C(OCC)C>[CH:20]([S:23]([O:19][N:18]=[C:9]([Cl:8])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:25])=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)S(=O)(=O)ON=C(Cl)c1c(Cl)cccc1Cl

Procedure:
A 3.6 (0.036 mol) sample of triethylamine was added slowly to a cooled mixture (ice bath) of 7.8 g (0.035 mol) alpha-chloro-2,6-dichlorobenzaldoxime (U.S. Pat. No. 3,234,255) and 5.5 g (0.035 mol) isopropylsulfonyl chloride in 125 ml diethyl ether. The reaction was slightly exothermic. The reaction mixture was filtered to remove a small amount of salts and the filtrate was evaporated under reduced pressure to give a yellow oil. The oil was chromatographed through a silica gel column with hexane/dichloromethane elution. O-isopropylsulfonyl-alpha-chloro-2,6-dichlorobenzaldoxime (white solid, m.p. 48°-50° C.) was eluted from the column with dichloromethane. Elemental analysis for C11H12Cl3NO3S showed: %S, calc. 9.3, found 8.1; %Cl, calc. 30.9, found 32.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:39][C:40]([F:48])([F:47])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([N:44]5[CH2:45][CH2:46][CH:41]([C:40]([F:48])([F:47])[F:39])[CH2:42][CH2:43]5)=[O:34])=[CH:31][CH:32]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Yield: 81.4 %

Procedure:
Stir a solution of 4-[(R)-3-(4′-Carboxy-3,5-dichloro-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 25) (0.1 g, 0.18 mmol), 4-(Trifluoromethyl)piperidine Hydrochloride (42 mg, 0.22 mmol), N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol), 1-Hydroxybenzotriazole (73 mg, 0.22 mmol) and 4-Methylmorpholine (0.08 mL, 0.73 mmol) in CH2Cl2 (3 mL) at room temperature for 6 hr. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.10 g (80%) of desired product. MS (m/e): 582 (M−BOC+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccc(Cl)cc1)N1CCC(CO)CC1

Procedure:
To a solution of 5.76 g (0.05 mol) of 4-piperidinemethanol and 4.75 g (0.06 mol) of pyridine in 50 mL of methylene chloride cooled to 0° add dropwise a solution of 10.4 g (0.055 mol) of 4-chlorobenzeneacetyl chloride in 25 mL of methylene chloride. When the addition is complete stir the reaction overnight at room temperature. After this time add 25 mL of 2N hydrochloric acid. Separate the layers and wash the methylene chloride layer with two 50 mL portions of saturated sodium bicarbonate solution and 25 mL of saturated sodium chloride solution then dry the methylene chloride layer over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][S:15][C:13]1[O:14][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[N:11][N:12]=1
Reactant: COc1ccc(CBr)cc1Cl
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: COc1ccc(CSc2nnc(-c3ccc4c(c3)CCO4)o2)cc1Cl
Yield: 87 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-chloro-4-methoxybenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 87%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:17][CH3:18].C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 78.4 %

Procedure:
Reaction of 4-aminobenzophenone (99 mg, 0.51 mmol) in THF (6 mL) with 4-propylbenzoyl chloride (100 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-propyl-benzamide (136 mg, 0.40 mmol, 78% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95).
Reaction SMILES: C(CC1N([C@@H:9]2[O:15][C@H:14](CO)[C@@H:12](O)[C@H:10]2[OH:11])C=NC=1C(N)=O)#N.C([O:24][C:25](=[O:27])[CH3:26])(=O)C.C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.CO>[CH3:9][C:10]([CH2:12][C:14]([CH2:26][C:25]([OH:24])=[O:27])=[O:15])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A suspension of 5-cyanomethyl-1-β-D-ribofuranosylimidazole-4-carboxamide (1.41 g, 5 mmol), acetic anhydride (15 ml) and p-dimethylaminopyridine (20 mg) was stirred at RT for 8 hr. Tlc (silica gel, CHCl3 --MeOH, 4:1) indicated three products. Additional p-dimethylaminopyridine (20 mg) and acetic anhydride (5 ml) was added and stirring continued at RT for 36 hr. The solution was evaporated in vacuo to a syrup which was dissolved in chloroform and placed on a column of silica gel (60 g). Elution with chloroform-methanol (20:1) provided the triacetate (2.0 g, 95%) as a white foam; pmr (DMSO-d6): δ 2.08, 2.10, 2.16 (s,3,COCH3), 4.40 (s,2,CH2), 6.13 (d,1,H1'), J = 5Hz, 7.39, 7.58 (s,2,NH), 8.19 (s,1,C2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].[NH3:10]>>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1](=[NH:10])[CH3:2])=[CH:4][CH:5]=1
Reactant: N
Reactant: C#Cc1ccc(C)cc1
Product: CC(=N)c1ccc(C)cc1
Yield: 60 %

Procedure:
1-p-tolylethanimine was prepared by reacting 1-ethynyl-4-methylbenzene and excess ammonia in the presence of 5 mol % of catalyst E (110° C., 18 h). The yield was 60%. 1H NMR (600 MHz, C6D6) δ=2.17 (3H, s, CH3), 2.18 (3H, s, CH3), 7.07 (2H, d, J=7.9 Hz, CH), 7.72 (2H, d, J=7.9 Hz, CH); 13C NMR (150 MHz, C6D6) δ=21.3 (CH3), 25.7 (NCCH3), 127.3 (CHortho), 129.5 (CHmeta), 136.9 (Cq,ipso), 140.8 (Cq,paraCH3), 173.7 (C═NH); HRMS (ESI): 134.0968 [(MH)+, 134.0970 (C9H12N)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9]1.C(N(CC)CC)C.C(NC1C=CC(S([N:41]=[N+:42]=[N-])(=O)=O)=CC=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(#N)C>[N+:41](=[C:11]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]1=[O:13])=[N-:42]
Reactant: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,5-Bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one (0.63 g, 2.3 mmol) was suspended in acetonitrile (10 mL), treated with triethylamine (0.27 mL, 2.7 mmol, 1.15 equiv) and cooled to 0° C. To the mixture was added 4-acetamidobenzenesulfonyl azide (0.61 g, 2.5 mmol, 1.1 equiv) and after 30 minutes at 0° C., the mixture was warmed to ambient temperature. After stirring for 30 minutes, the mixture was poured into sodium carbonate (25 mL, aqueous saturated) and sodium hydroxide (10 mL, 1 N aqueous) and extracted with dichloromethane (2×125 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.