Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].N1C=CN=C1.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([Si:24]([CH3:26])([CH3:25])[O:11][CH2:10][CH2:9][S:8][C:6]1[N:7]=[C:2]([CH3:1])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1nc(SCCO)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc(SCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
A mixture of 2-(6-methyl-5-nitro-pyridin-2-ylsulfanyl)-ethanol (60% pure, 3.25 g, 9.1 mmol), 1H-imidazole (1.24 g, 18.2 mmol), and tert-butylchlorodimethylsilane (2.75 g, 18.2 mmol) in 20 mL DMF was stirred at room temperature for 4 h. Solution was concentrated and residue was extracted with water and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was purified by column chromatography (hexane/AcOEt 30:1) to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethylsulfanyl]-2-methyl-3-nitro-pyridine as a yellow oil (2.39 g, 48%). 1HNMR (CDCl3, 400 MHz) δ 0.8 (s, 6H), 0.90 (s, 9H), 2.85 (s, 3H), 3.39-3.42 (t, J=6.7 Hz, 2H), 3.85-3.89 (t, J=6.7 Hz, 2H), 7.13-7.15 (d, J=8.7 Hz, 1H), 8.10-8.13 (d, 1H). Exact mass calculated for C14H24N2O3SSi 328.13 found 329.1 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([Cl:17])[CH:10]=2)=[O:5])C.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[C:28]([C@@H:20]([NH:19][C:7]1[C:6]([C:4]([OH:3])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([Cl:17])=[C:12]([Cl:16])[CH:13]=2)[N:8]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cc(Cl)c(Cl)cc2nc1N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 130 °C
Reaction time: 22 h
Yield: 38 %

Procedure:
A mixture of 2,6,7-trichloroquinoline-3-carboxylic acid ethyl ester (80 mg, 0.26 mmol), L-phenylalanine (80 mg, 0.52 mmol) and potassium carbonate (180 mg, 1.31 mmol) in DMF (1 mL) is stirred for 22 h at 130° C. in closed reaction vial. After cooling the reaction mixture is diluted with water, acidified by addition of 2N HCl, and the precipitated solid is collected on filter, washed with water and air dried to give the title compound (40 mg, 38%) as yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[C:4]=1[CH3:11])#[N:2].Cl.[NH2:13][OH:14].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl.C1COCC1>[C:1]([C:3]1[C:4]([CH3:11])=[C:5]([C:9](=[NH:10])[NH:13][OH:14])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1c(C#N)cccc1C#N
Reactant: NO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1C(=N)NO
Temperature: 50 °C
Reaction time: 7 h
Yield: 14.6 %

Procedure:
A suspension of 2,6-dicyanotoluene (25.0 g, 176 mmol), hydroxylamine hydrochloride (73.0 g, 1.06 mol) and triethylamine (142 g, 1.41 mol) in chloroform (500 ml) was stirred at 50° C. for 7 h, then allowed to stand at room temperature overnight. The reaction mixture was cooled in ice, treated with 5M HCl to pH1 and extracted three times with chloroform. The aqueous was extracted with THF (×7), cooled in ice, raised to pH4 with 40% NaOH and extracted with THF (×3). The latter THF extracts were combined and evaporated to dryness to give a buff solid consisting of the product and approximately a third of an equivalent of triethylamine (11.0 g). 1H NMR (400 MHz, d4-MeOH) δ (inter alia) 7.70-7.76 (1H, m), 7.57-7.63 (1H, m), 7.35-7.62 (1H, m), 2.58 (3H, s); MS (ES) C9H9N3O requires 175; found 176 [M+H]+. The former seven extracts of THF were combined, evaporated to dryness and dissolved in water. The aqueous solution was extracted twice with chloroform, adjusted to pH4 and extracted with THF (×3). Evaporation of the combined THF extracts gave a further 4.5 g of product.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:14][C:15]1[C:16]([O:23][CH3:24])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].[F-].[K+].[OH-].[Na+]>CN(C=O)C>[CH:18]([C:17]1[C:16]([O:23][CH3:24])=[C:15]([CH:22]=[CH:21][CH:20]=1)[O:14][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[O:19]
Reactant: COc1c(O)cccc1C=O
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C=O)cccc1Oc1nc(C(F)(F)F)ccc1C#N
Yield: 97 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (0.34 g, 1.6 mmol), 3-hydroxy-2-methoxybenzaldehyde (0.25 g, 1.6 mmol) and potassium fluoride (0.29 g, 4.9 mmol) were heated with stirring in dry DMF (4 mL) at 120° C. for 3 h. The reaction mixture was cooled, poured into 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (3×), water (3×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-(3-formyl-2-methoxyphenoxy)-6-(trifluoromethyl)nicotinonitrile (0.50 g, 94%) as a yellow solid.
Reaction SMILES: [C:1]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:50])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:48])[CH2:36][CH2:37][CH2:38][N:39](C(OC(C)(C)C)=O)[CH3:40])=[CH:31][CH:30]=2)[CH3:27])[CH3:19])[CH2:12][CH2:11]1.[ClH:57].O1CCOCC1.CO>O1CCOCC1>[ClH:57].[ClH:57].[ClH:57].[C:1]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:50])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:49])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:48])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40])=[CH:31][CH:30]=2)[CH2:12][CH2:11]1
Reactant: CN(CCCCCC(=O)N(C)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)Cc1ccc(C(=O)CCCN(C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNCCCC(=O)c1ccc(CN(C)CCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
The compound (460 mg, 0.598 mmol) obtained in Example 78b was dissolved in 1,4-dioxane (6 mL), a 4 N hydrochloric acid-dioxane solution (1.49 mL, 5.98 mmol) and methanol (1 mL) were added under ice cooling, and the mixture was stirred at room temperature for 5.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to give crude 1-(2-{methyl[6-(methyl{-4-[4-(methylamino)butanoyl]benzyl}amino)hexanoyl]amino}ethyl)piperidin-4-yl biphenyl-2-ylcarbamate trihydrochloride. The resulting crude product was used to give the title compound (101 mg; yield, 26%) as a white solid according to the method described in Example 11e.
Reaction SMILES: [CH:1]([N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)N1CC2CN(C(=O)OC(C)(C)C)CCN2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CC2CNCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (compound 104-C-1) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. After the reaction mixture was stirred at rt for 1 hour, the solvent was removed in vacuum to give the crude product 104-C, which was used directly in the next step.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][NH:5]1)#[N:2].[H-].[Na+].[O:11]1[CH:17]2[CH:12]1[C:13]([CH3:25])([CH3:24])[O:14][C:15]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][C:16]=12>CS(C)=O>[C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:17]1[C:16]2[CH:18]=[C:19]([C:22]#[N:23])[CH:20]=[CH:21][C:15]=2[O:14][C:13]([CH3:24])([CH3:25])[C@H:12]1[OH:11])#[N:2]
Reactant: N#CN=C1NCCN1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-cyanoiminoimidazolidine (0.42 g) in dimethyl sulfoxide (12.5 ml) was added 60% sodium hydride (0.15 g) under water-cooling and the mixture was stirred at room temperature for 0.5 hours. 3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.50 g) was added portionwise thereto. After being stirred at room temperature overnight, the mixture was poured into ice-brine (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was pulverized with chloroform and recrystallized from ethanol to give trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.15
Reaction SMILES: Br[C:2]#[C:3][C:4]1[N:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]=1[CH2:17][O:18][CH3:19])=[C:13]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:12]=[CH:11][CH:10]=3.O1CCCC1.C([Li])(C)(C)C.O>CCCCC>[CH2:21]([O:20][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[C:15]1[C:16]([CH2:17][O:18][CH3:19])=[C:4]([C:3]#[CH:2])[N:5]=[CH:6][C:7]=1[NH:8]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COCc1c(C#CBr)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: C1CCOC1
Product: C#Cc1ncc2[nH]c3cccc(OCc4ccccc4)c3c2c1COC
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A solution of 0.164 g of 1-bromo-2-(5-benzyloxy-4-methoxymethyl-beta-carbolin-3-yl)acetylene in 5 ml of abs. tetrahydrofuran is cooled under N2 atmosphere to -78° C. and mixed with 0.46 ml of a 1.4 molar solution of tertbutyllithium in pentane. After 1 hour stirring at -78° C. the reaction mixture is heated to room temperature and stirred for 1.5 hours more. Then it is carefully decomposed with water and extracted with dichloromethane. The organic phases are combined, dried and the solvent evaporated. The residue is chromatographed over silica gel with acetone/hexane=1+1 as eluant. 0.056 g of 5-benzyloxy-3-ethinyl-4-methoxymethyl-beta-carboline with a melting point of 207°-209° is obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:20]3=[N:21][C:22]4[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]=4[N:19]3[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][N:8]=1)(=O)=O.[CH3:36][N:37](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:28][C:27]1[C:22]2[N:21]=[C:20]3[N:14]([C:10]4[C:11]([CH3:13])=[CH:12][C:7]([C:36]#[N:37])=[N:8][CH:9]=4)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23]=2[C:24]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][CH:26]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(OS(=O)(=O)C(F)(F)F)cc1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C#N)cc1C
Temperature: 120 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Under argon atmosphere a mixture of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-4-methylpyridin-2-yl trifluoromethanesulfonate (Example 58; 285 mg, 0.537 mmol), zinc cyanide (94.5 mg, 0.805 mmol), tetrakis(triphenylphosphine)palladium(0) (62.1 mg, 0.0537 mmol) and N,N-dimethylformamide (2.7 mL) was stirred at 120° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (166 mg, 0.407 mmol, 76%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1I.FC1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.[Pd]>[F:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cc(Br)ccc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Fc1ccccc1
Product: Fc1cc(Br)ccc1-c1ccccc1
Yield: 10 %

Procedure:
Using methodology generally similar to the above examples, 1.22 g of phenylboronic acid in about 5 ml of ethanol, 3 g of 2-fluoro-4-bromoiodobenzene, 20 g of fluorobenzene, 0.2 g of 5% Pd on carbon catalyst, and 10 ml of 2 molar Na2CO3 were combined and stirred rapidly (without a nitrogen purge) at 25° C. for 65 hours. The desired 2-fluoro-4-bromobiphenyl was produced in about 10% yield with only partial conversion of the starting materials, considerable byproduct formation, but no observed terphenyl formation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Br:8])[C:3]=1[OH:9].CCO[C:13]([S-])=[S:14].[K+]>CCO>[Br:8][C:4]1[C:3]2[O:9][C:13]([SH:14])=[N:1][C:2]=2[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccnc(Br)c1O
Agent: [K+]
Solvent: CCO
Product: Sc1nc2ccnc(Br)c2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.34 g (7.09 mmol) 4-amino-2-bromo-pyridin-3-ol are dissolved in 13 ml EtOH and 1.86 g (11.3 mmol) potassium ethyl xanthogenate are added. This mixture is stirred for 18 h at reflux temperature. After cooling to room temperature, the reaction mixture is concentrated in vacuo and 5 ml water are added. With the addition of acetic acid, a pH of 5 is adjusted. The product starts to crystallize and is filtered off, washed 2× with water and dried to afford the title compound.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCCC2)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (66%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:6]=1>C(O)C>[F:19][C:4]([F:3])([F:18])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[OH:17])[CH:6]=1
Reactant: O=C1CCCC1Cc1cc(C(F)(F)F)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCC1Cc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (0.117 g, 3.08 mmol) was added to a solution of 2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-one (0.375 g, 1.54 mmol) in ethanol (10 ml). The reaction was stirred at room temperature for 3 hours and then quenched with water (5 mL) and 2M HCl (aq., 5 ml). The organics were extracted with ethyl acetate (2×30 ml) and the combined organics were washed with brine (10 ml), dried over magnesium sulfate, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-35% ethyl acetate/petrol) to afford the title compound as two diastereomers.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])=[N:8][CH:9]=1)[CH3:24]
Reactant: CC(C)=CCOc1ccc(C(=O)O)cn1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)nc1
Yield: 68.1 %

Procedure:
In a manner identical to Example 15, 6-prenyloxynicotinic acid (0.70 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.90 g), thereby yielding 0.73 g(68%) of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1cc(F)ccc1F
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1cc(F)ccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 2,5-difluorophenol: 1H-NMR (CDCl3) δ 7.95 (1H, d, J=2.8 Hz), 7.46 (1H, dd, J=8.8, 2.8 Hz), 7.20–7.10 (1H, m), 6.95 (1H, d, J=8.8 Hz), 6.85–6.73 (1H, m), 6.68–6.56 (1H, m), 3.85 (3H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc(N)cn1
Temperature: 150 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
To a solution of 5-chloropyrazin-2-amine (0.2 g, 1.54 mmol) in MeOH (3 mL) was added Cu powder (0.13 g, 2.07 mmol), followed by a solution of sodium methoxide in MeOH (0.38 mL, 1.75 mmol). The reaction mixture was stirred at 150° C. in a sealed tube for 24 h. The reaction mixture was then filtered through Celite, and the filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.13 g, 67%). LCMS (ES+) 126 (M+H)+, RT 1.06 minutes (method 1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:60]1[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][C:61]=1[C:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:68]>C1(C)C=CC=CC=1>[Cl:66][C:63]1[CH:64]=[CH:65][C:60]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:61]([C:67]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)=[O:68])[CH:62]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Br
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1N1CCNCC1
Temperature: 110 °C

Procedure:
Piperazine (3.6 g, 42.5 mmol), Pd(II)acetate (0.007 g, 0.043 mmol), sodium t-butoxide (0.22 g, 2.4 mmol) and BINAP (0.042 g, 0.068 mmol) were stirred at room temperature in 10 mL dry toluene for 15 min. (2-Bromo-5-chloro-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol) in 10 mL dry toluene was then added into the reaction mixture. The reaction mixture was refluxed at 110° C. for 20 hrs, filtered through a celite bed, washed with toluene, concentrated, taken in ethyl acetate and extracted with 1.5 (N)HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (eluted with CHCl3-MeOH) afforded the title compound as product.
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[O:10][C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>CO>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][CH:13]([C:11]3[O:10][C:9](=[O:28])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:12]=3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1
Reactant: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)nn1Cc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: Nc1ccc(N2CCC(c3nn(Cc4ccccc4)c(=O)o3)CC2)cc1
Yield: 87.8 %

Procedure:
5-[1-(4-Nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a 1.16 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 4.8 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6c, 1.42 g, 94%). Nitro compound (6c, 1.52 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7d, 1.23 g, 88%). To a stirred solution of 5-nitro2-furanoic acid in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7d, 0.35 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8d, 405 mg, 83%).