Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[F:13][C:14]([F:22])([F:23])[C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:10](=[O:12])[CH2:9][C:7]#[N:8])=[CH:20][CH:21]=1
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Phosphorus pentachloride (83.3 g; 0.40 mol) is introduced into a solution of cyanoacetic acid (34.0 g; 0.40 mol) in 1,2 l of dichloromethane and the mixture is heated under reflux for 30 minutes. 4-Trifluoromethylaniline (41.0 g, 0.26 mol) is then introduced into said mixture within about 10 minutes and the reaction mixture is heated under reflux for 2 hours. After cooling to 20° C., the reaction mixture is treated with 500 ml of water and then stirred for 30 minutes. The aqueous phase is neutralized with sodium carbonate and the precipitate is filtered off with suction. The filter cake is washed with water and dried. 55.2 g of N-(4-trifluoromethylphenyl)cyanoacetamide are thus obtained in crystalline form. Melting point: 194°-195.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10](=[O:19])[NH:9][N:8]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:30]([O:29][C:27]([CH2:26][N:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]1=[O:19])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CNc2n[nH]c(=O)c3ccc(C#N)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nn(CC(=O)OC(C)(C)C)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 153.6 %

Procedure:
4-(3-Chloro-4-methoxybenzyl)amino-6-cyanol-1(2H)-phthalazinone (0.20 g) prepared in Example 21 was dissolved in 5 ml of N-methyl-2-pyrrolidinone, followed by the addition of 0.14 g of t-butyl bromoacetate and 0.24 g of potassium carbonate. The obtained mixture was stirred at 80° C. for 4 hours and poured into water, followed by extraction with ethyl acetate. The organic phase was washed with water twice and with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by vacuum distillation. The title compound (0.41 g) was obtained as a yellow crystal.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:25][C:24]3[C:20]4=[CH:21][O:22][N:23]=[C:19]4[CH:18]=[CH:17][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1>CS(C)=O>[NH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32]([C:29]2[CH2:30][CH2:31][N:26]([CH2:12][CH:13]3[O:25][C:24]4[C:20]5=[CH:21][O:22][N:23]=[C:19]5[CH:18]=[CH:17][C:16]=4[O:15][CH2:14]3)[CH2:27][CH:28]=2)=[CH:33]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nocc4c3O2)cc1
Solvent: CS(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4nocc4c3O2)C1
Temperature: 77.5 °C

Procedure:
(2R)-2,3-Dihydro[1,4]dioxino[2,3-e][2,1]benzisoxazol-2-ylmethyl 4-methyl-benzenesulfonate (0.60 g, 1.66 mmole) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.98 g, 4.90 mmole) were combined in 30 mL of DMSO under nitrogen. This solution was heated to 75-80° C. under nitrogen for 6 hours. After completion, the reaction was cooled to room temperature and partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed and washed with brine, dried over magnesium sulfate and concentrated in vacuum. The crude residue was column chromatographed on silica gel using methylene chloride to remove impurities and 1% methanol/methylene chloride to elute the product. Upon evaporation of the product fractions, 0.47 g (73%) of the (S)-enantiomer of the title compound was obtained as a white solid, m.p. 110° C.
Reaction SMILES: Cl[SiH:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:10]([C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]=1[OH:40])[C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]=1[OH:25].C(N(CC)CC)C>>[C:32]([C:30]1[CH:29]=[C:28]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:27]2[O:40][SiH:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:25][C:12]3[C:13]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:14][C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:16][C:11]=3[S:10][C:26]=2[CH:31]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)c1cc(Sc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: Cl[SiH](Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[SiH](c1ccccc1)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)S2
Yield: 40.8 %

Procedure:
Utilizing the procedure of Example 1, this compound is prepared from 5.3 grams (0.03 mole) dichlorophenylsilane, 13.3 grams (0.03 mole) 2,2'-thio-bis(4,6-di-t-butylphenol), and 6.1 grams (0.06 mole) triethylamine. Recrystallization from acetone gives 6.7 grams (41% yield) of white solid, mp 175°-177° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27](Cl)([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]([Cl:26])[C:20]([C:22]([F:23])([F:25])[F:24])=[CH:21][C:16]=3[N:15]=[C:14]2[C:27]([N:31]=[N+:32]=[N-:33])([CH3:29])[CH3:28])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(-n2c(C(C)(C)Cl)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCc1ccc(-n2c(C(C)(C)N=[N+]=[N-])nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 42 %

Procedure:
A mixture of 2-{4-[6-chloro-2-(1-chloro-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl acetate (step 1, 273 mg, 0.68 mmol), sodium azide (88 mg, 1.36 mmol), KI (112 mg, 0.68 mmol) in DMF (8 ml) was stirred under nitrogen at room temperature for 5.5 h. The reaction mixture was poured into water (5 ml) and the aqueous mixture was extracted with ethyl acetate(30 ml). The organic layer was washed with water (5 ml) and brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2/1) to afford 133 mg (42%) of the title compound as yellow oil.
Reaction SMILES: [C:1]([C:11]1[S:12][C:13]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:14][C:15]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:18])([O:3]CC1C=CC=CC=1)=[O:2]>CCO.[Pd]>[C:1]([C:11]1[S:12][C:13]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:14][C:15]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:18])([OH:3])=[O:2]
Reactant: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2C(=O)O)cc1
Yield: 90.2 %

Procedure:
To a solution of N-(2-carbobenzyloxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.19 g, 0.40 mmol) in EtOH (19 mL) was added 10% Pd/C (0.010 g). The resulting suspension was treated with H2 (52 psi) in a Parr® shaker for 18 h. The slurry was filtered through a pad of Celite® and concentrated under reduced pressure to afford N-(2-carboxy-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.12 g, 90%):1H NMR (d6-DMSO) δ13 (s, 9H), 2.2 (s, 3H), 7.1 (d, 2H), 7.4 (d, 2H), 7.8 (s, 1H); FAB-LRMS m/z) 333 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:23]=[S:24]>CN(C)C=O>[C:25]1([NH:22][C:23]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12]2)=[S:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(C(=S)Nc3ccccc3)c3ncccc23)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine 1 (50 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (4 mL). Sodium hydride (10 mg, 0.24 mmol, 60% dispersion in mineral oil) was added. The reaction mixture was stirred for 15 minutes at room temperature. 1-Isothiocyanatobenzene (35 μL, 0.29 mmol) was added and the reaction mixture was stirred for 40 minutes at room temperature. The product was concentrated and the residue was partitioned between brine and ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered, and concentrated to provide a solid. The solid was washed with a minimum of methanol and dried in vacuo to provide 41, (38 mg, 49%). MS(ESI) [M+H+]+=390.2.
Reaction SMILES: [ClH:1].CO.[CH2:4]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C3CCCCO3)=[O:26])=[CH:19][CH:18]=2)[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[ClH:1].[ClH:1].[CH2:4]([N:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])=[CH:19][CH:18]=2)[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1)NO
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of 10% HCl-MeOH solution (0.75 ml) was added to a mixture of (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170 mg) in MeOH 3 ml) and stirred at 15-25° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was triturated with small amount MeOH and acetone and the precipitate was collected by filtration to give (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-hydroxyacrylamide dihydrochloride (107 mg)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:13]=[O:14])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc(Br)ccc2c1
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc2cc(-c3ccccc3C=O)ccc2c1
Yield: 91 %

Procedure:
Under an atmospheric argon gas flow, 2-bromo-6-methylnaphthalene in an amount of 6.6 g (30 mmol), 2-formylphenylboronic acid in an amount of 5.4 g (36 mmol), (tetrakistriphenylphosphine)palladium in an amount of 0.7 g (0.6 mmol), 2N sodium carbonate aqueous solution in an amount of 45 milliliter and dimethoxyethane in an amount of 90 milliliter were placed into a three neck flask with a cooling pipe and having a capacity of 500 milliliter, and the resultant solution was refluxed under heating for 8 hours. After the reaction terminated, adding water in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=60/40), and as a result, 6.7 g of aimed compound (white crystal) was obtained (yield: 91%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:41])=[CH:4][C:5]2[C:10]3[C:11]4[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:29][C@H:28]([CH2:30][OH:31])[C:27]([F:33])([F:32])[C@H:25](O)[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:34])=[C:16]([F:35])[CH:15]=5.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[C:3]([F:41])=[CH:4][C:5]2[C:10]3[C:11]4[C:38](=[O:39])[NH:37][C:36](=[O:40])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:29][C@@H:28]7[CH2:30][O:31][C@@H:25]([C:27]7([F:33])[F:32])[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:34])=[C:16]([F:35])[CH:15]=5
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C(F)(F)[C@H](O)[C@H]1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@@H]2CO[C@H]([C@H]1O)C2(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
To a solution of 2,3,9,10-tetrafluoro-12-(4-deoxy-4, 4-difluoro-β-D-glucopyranosyl)-6, 7, 12, 13-tetrahydro(5H)indolo[2, 3-a]pyrrolo[3, 4-c]carbazole-5, 7-dione (0.035 g, 0.060 mmol) in 4 mL of dry THF was added triphenylphosphine (0.048 g, 0.18 mmol) and DIAD (0.035 mL, 0.18 mmol), at room temperature under Ar. The resulting reddish-orange solution was stirred at room temperature for 18 h and then it was partitioned with ethyl acetate-water. The organic phase was separated, washed (brine), dried (Na2SO4) and evaporated to give a yellow gum. This residue was purified by prep. tlc (20×20 cm×0.5 mm SiO2/THF-hexane, 1:1) and the major fraction was repurified by prep. hplc to give the title compound (0.009 g, 29%) as a yellow solid: 1H NMR (acetone-d6, 400 MHz) δ 10.67 (s, 1H), 9.83 (s, 1H), 8.88 (m, 1H), 8.73 (m, 1H), 7.56 (m, 2H), 6.44 (m, 1H), 4.91 (m, 2H), 4.47 (d, J=10.0 Hz, 1H), 4.41(d, J=11.0 Hz, 1H), 4.27 (m, 1H); MS (ESI−) m/e 560 (M−H)-; HPLC: 91.1% (320 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=O)s2)cc1
Reactant: BrCc1ccccc1
Product: COc1ccc(-c2ccc(C(O)c3ccccc3)s2)cc1
Yield: 64 %

Procedure:
The title compound was prepared from the product of step 1 (0.56 g, 2.55 mmol) and benzyl bromide (0.5 g, 3.2 mmol) using the procedure of Example 159, step 2 with 64% yield (0.6 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([O:22]C)=O)[CH:17]=[CH:18][CH:19]=3)[N:15]=2)=[CH:7][CH:6]=1)[CH3:3].O.[NH3:25]>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([NH2:25])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:15]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: COC(=O)c1cccc2oc(-c3ccc(CN(C)C)cc3)nc12
Reactant: N
Solvent: O
Product: CN(C)Cc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
Methyl 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxylate (40 mg, 0.13 mmol) and ammonia water (17.2 mg, 0.52 mmol) were added and the mixture was stirred at 30° C. for 1 h. The resulting mixture was evaporated under reduced pressure and purified by pre-HPLC. 2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide (16 mg) was obtained, yield 41%. LC-MS (ESI) m/z: 296 (M+1)+. 1H-NMR (400 MHz, DMSO-d6): δ 2.94 (s, 6H), 4.46 (s, 2H), 7.57-7.58 (m, 1H), 7.75-7.77 (m, 2H), 7.93 (brs, 1H), 8.09 (brs, 1H), 8.43-8.44 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:15]=1
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(N2CCNCC2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Piperazine (1.13 g) and 2-chloro-6-methylnicotinonitrile (500 mg) were dissolved in DMF (15 ml), and K2CO3 (1.36 g) was added thereto, followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-methyl-2-piperazin-1-ylnicotinonitrile (628 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16]Br)[CH:3]=1.C(N(CC)CC)C.Cl.[C:26]([O:30][C:31](=[O:34])[CH2:32][NH2:33])([CH3:29])([CH3:28])[CH3:27]>C(#N)C>[C:26]([O:30][C:31](=[O:34])[CH2:32][NH:33][CH2:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc2cc(Br)cc(CNCC(=O)OC(C)(C)C)c2nc1OC

Procedure:
850 mg (2.35 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline, 0.982 ml of triethylamine and 719 mg of glycine tert-butyl ester hydrochloride are dissolved in 15 ml of acetonitrile and the solution is stirred at reflux for 18 hours. The mixture is concentrated by evaporation and the residue is dissolved in diethyl ether and washed with aqueous 5% sodium carbonate solution and brine. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate and petroleum ether (1:2). The title compound is obtained in the form of a yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]#[N:15])[CH:9]=[CH:10][C:11]=1[F:12].C(=O)([O-])O.[Na+]>>[N+:1]([C:9]1[CH:10]=[C:11]([F:12])[C:6]([F:5])=[CH:7][C:8]=1[CH2:13][C:14]#[N:15])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: N#CCc1ccc(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#CCc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Fuming nitric acid (25 ml) was stirred with cooling (ice/water bath) and 3,4-difluorophenylacetonitrile (5 g, 32.7 mmol) was added dropwise. The mixture was left to stir for 15 h and was then poured onto ice. The mixture was neutralised with sodium hydrogen carbonate and extracted with dichloromethane. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to give 2(2'-nitro-4',5'-difluorophenyl)-acetonitrile as a yellow oil which was immediately in ethanol/acetic acid (19:1) and hydrogenated over 10% palladium on charcoal at 65 p.s.i. The reaction mixture was filtered and concentrated under reduced pressure. The oily residue was taken up in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The combined organic phases were dried (MgSO4), filtered and concentrated under reduced pressure to give 5,6-Difluoroindole as a yellow solid. Mass spectroscopy showed 154.1 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[N:12]3[C:15](=[O:22])[C:16]([CH3:21])([CH:18]([CH3:20])[CH3:19])[N:17]=[C:11]3[C:7]2=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH2:25]([OH:31])[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>O1CCCC1>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([C:11]2[NH:12][C:15](=[O:22])[C:16]([CH:18]([CH3:19])[CH3:20])([CH3:21])[N:17]=2)=[C:6]([CH:5]=1)[C:13]([O:31][CH2:25][C:26]1[O:30][CH:29]=[CH:28][CH:27]=1)=[O:14])(=[O:3])[CH3:2]
Reactant: OCc1ccco1
Reactant: CC(=O)c1cc2c(nc1C)C1=NC(C)(C(C)C)C(=O)N1C2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)c1cc(C(=O)OCc2ccco2)c(C2=NC(C)(C(C)C)C(=O)N2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.0 g of 7-acetyl-2,8-dimethyl-2-isopropyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]-pyridine-3(2H),5-dione in 50 mL tetrahydrofuran is added dropwise to a preformed mixture of 0.03 g sodium hydride and 0.35 mL furfuryl alcohol in 50 mL tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, acidified with acetic acid, and concentrated in vacuo. The residue is chromatographed on silica gel using 5% ethyl acetate in methylene chloride as eluant to afford the desired product. Recrystallization from methylene chloride-hexanes gives a solid, mp 133°-136°.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].CCOCC>C(O)(=O)C>[NH2:3][C:4]1[C:12]([CH3:13])=[CH:11][C:10]([I:1])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: ClI
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(I)cc(C(=O)O)c1N

Procedure:
Iodine monochloride (28.9 g) was added over 0.5 hours to a stirred solution of 2-amino-3-methylbenzoic acid (24.5 g) (Aldrich Chemical Co. Ltd.) in acetic acid (250 cm3). After 24 hours ether (250 cm3) was added and the mixture was filtered. The solid material was dried in vacuo to afford the title compound, m.p. 214° (38.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:6]=1)=[O:4]>C(O)(=O)C.O=[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:6]1)=[O:4]
Reactant: COC(=O)c1cccc(C=CC(=O)OC(C)(C)C)n1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCCC(CCC(=O)OC(C)(C)C)N1
Reaction time: 72 h

Procedure:
Compound 2 (1.0 g) is dissolved in glacial acetic acid (10 ml) and PtO2 (100 mg) is added. Hydrogenation is carried out in Parr shaker at 55 psi for 3 days. The catalyst is removed by filtration through Celite, and the solvent is evaporated to give the desired product as a yellow oil. 1H NMR (CD3OD) δ 3.73 (s, 3H), 3.40-3.33 (m, 1H), 2.61-2.52 (m, 1H), 2.34-2.29 (m, 2H), 2.03-1.99 (m, 1H), 1.93-1.88 (m, 1H), 1.76-1.68 (m, 3H), 1.50-1.33 (m, 11H), 1.11-1.02 (m, 1H).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH:12]=[CH:13][O:14]C)[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(OCC)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:12][CH:13]=[O:14])[CH2:8][CH2:9][C:10]#[N:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC=CC(CCC#N)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: N#CCCC(CC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of 4,4-diphenyl-6-methoxyhex-5-enenitrile (4.0 g, 14.4 mmol) in diethylether (60 mL) was added HCl (2 mL, 37 %). The reaction mixture was stirred at room temperature for 16 hr and then the solvent was evaporated in vacuo . The residue was dissolved in dichloro- methane and filtered through a plug of silica gel to give the desired aldehyde as an oil (3.78 g, 99%): 1H-NMR (CDCl3, δ): 2.03-2.10 (m, 2H), 2.56- 2.64 (m, 2H), 3.12 (d, J=3 Hz, 2H), 7.14-7.41 (m, 1OH), 9.34 (t, J=3 Hz, 1H). Anal. Calcd for C1 8HI7NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.10; H. 7.02; N. 4.78.