Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.C([N:75]1[CH2:80][CH2:79][N:78]([CH:81]2[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]2)[CH2:77][CH2:76]1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13](=[O:14])[N:84]1[CH2:85][CH2:86][CH:81]([N:78]2[CH2:79][CH2:80][NH:75][CH2:76][CH2:77]2)[CH2:82][CH2:83]1)[CH3:2]
Reactant: c1ccc(CN2CCN(C3CCNCC3)CC2)cc1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 500 mg (1.02 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid, 320 mg (1.09 mmol) TBTU, 0.22 mL (0.97 mmol) ethyldiisopropylamine and 45 mL THF was stirred for 1 h at RT, then combined with 310 mg (1.20 mmol) 1-benzyl-4-piperidin-4-yl-piperazine and 5 mL DMF and stirred overnight. The reaction mixture was diluted by the addition of 30 mL EtOAc, extracted with 30 mL of a 15% K2CO3 solution and the organic phase was dried. The organic phase was evaporated down under reduced pressure and the residue purified by chromatography on silica gel. The intermediate product fractions were evaporated down under reduced pressure, the residue remaining (260 mg) was dissolved in 20 mL MeOH and hydrogenated in the autoclave in the presence of 50 mg Pd/C (10%) at 50° C. and 3 bar hydrogen pressure until the calculated volume of hydrogen had been taken up. The catalyst was filtered off, the solvent eliminated under reduced pressure and the residue purified by chromatography on silica gel. The product fractions were evaporated down under reduced pressure, the residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][C:3]=1[CH2:11][CH2:12][CH3:13].Cl[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C:3]1[CH:4]=[C:5]([C:8]2[S:10][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:9]=2)[CH:6]=[CH:7][C:2]=1[OH:1])[CH2:12][CH3:13]
Reactant: CCCc1cc(C(N)=S)ccc1O
Reactant: O=C1CCCCC1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1O
Yield: 96.9 %

Procedure:
A suspension of 4-hydroxy-3-propyl-thiobenzamide (5 g, 0.026 mol) (Example 34), 2-chlorocyclohexanone (4.07 g, 0.031 mol), and p-toluenesulfonic acid monohydrate (0.244 g, 1.28 mmol) in anhydrous toluene (100 mL) was heated to reflux in a Dean-Stark apparatus under argon for 12 h. At about 90° C., the mixture became a red orange oil and after 4 h of refluxing, precipitation was observed. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). The organic layer was washed successively with saturated sodium bicarbonate (2×50 mL), water (2×50 mL), brine, dried over sodium sulfate, and concentrated to give the desired product as a tan solid (6.89 g, 98%). LC/MS m/z 274.3 (M+H)+, RT 2.99 min. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.53-7.44 (m, 2H), 6.81 (d, 1H), 2.72-2.68 (m, 4H), 2.54-2.49 (m, 2H), 1.78 (b, 4H), 1.58-1.53 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][CH3:13].[F:14][C:15]1[C:20](O)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:14][C:15]1[C:20]([O:10][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][CH3:13])[CH:4]=2)=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=1[F:25]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
A mixture of 4-hydroxy-3-methoxyphenylacetic acid (4.65 g), pentafluorophenol (4.2 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.9 g) and methylene chloride (50 ml) was stirred at room temperature for 18 hours. The reaction solution was washed with water, and the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give 4-hydroxy-3-methoxyphenylacetic acid pentafluorophenyl ester (7.8 g). This product is dissolved in ethyl acetate (80 ml), and thereto is added 3-iodeaniline (7.4 g). The mixture is heated at 60° C. under stirring for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (6.2 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>>[ClH:28].[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([S:19]([C:16]2[S:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:18][CH:17]=2)(=[O:20])=[O:21])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(S(=O)(=O)c3cccnc3)s2)CC1
Agent: Cl
Product: O=S(=O)(c1cccnc1)c1cnc(N2CCNCC2)s1
Yield: 99 %

Procedure:
Prepared in analogy to example 4 (d) from 4-[5-(pyridine-3-sulfonyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and hydrogen chloride solution. The crude material was purified by recrystallisation from ether to afford the title compound as an off-white crystalline solid (yield 99%). MS (m/e): 311.0 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:12]=[CH:11][C:9]([N:10]2[C:18]([CH3:19])=[CH:17][CH:13]=[C:14]2[CH3:16])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(=O)CCC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-n2c(C)ccc2C)cc1
Temperature: 150 °C

Procedure:
A mixture of 4-ethoxycarbonylaniline (82.6 g), acetonylacetone (68.5 g) and concentrated sulfuric acid (one drop) were heated at 150° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water, followed by drying and concentrating, whereby 1-(4-ethoxycarbonylphenyl)-2,5-dimethylpyrrole was obtained.
Reaction SMILES: FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(C[C:14]1[C:15]([N:24]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)CC)=NC2C(C=1)=CC=CC=2)C1NN=NN=1.[OH-].[Na+].ClCCl.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:28]1([CH2:27][NH:24][CH2:15][CH3:14])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCN(CC1CCCC1)c1nc2ccccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: ClCCl
Solvent: O
Product: CCNCC1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
To a suspension of (3-{[(3,5-bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-methyl}-quinolin-2-yl)-cyclopentylmethyl-ethyl-amine (0.133 g, 0.230 mmol in water (4 mL) was added sodium hydroxide (0.009 g, 0.230 mmol), and this mixture was stirred for 15 min at RT, followed by the addition of dichloromethane (4 mL). To this reaction mixture was added dimethyl sulfate (0.030 g, 0.241 mmol), followed by the addition of tetrabutylammonium bromide (0.003 g, 0.011 mmol). This mixture was stirred for 24 h. The organic layer was separated from aqueous layer, the aqueous layer was extracted with DCM (3×10 mL), the combined organic layer was washed with brine and dried over sodium sulfate, and concentrated under vacuum to afford the crude residue. This residue was purified by column chromatography over 100-200 mesh silica gel using 8% ethyl acetate and petroleum ether to afford (3-{[3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]-methyl-}-quinoline-2-yl)-cyclopentylmethyl-ethyl amine (0.030 g, yield: 22%).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].[CH:14]1([CH2:20]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([CH2:20][N:5]2[C:6]([CH3:9])=[C:7]([CH3:8])[C:3]([CH:1]=[O:2])=[C:4]2[C:10]([O:12][CH3:13])=[O:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: BrCC1CCCCC1
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC1CCCCC1

Procedure:
The title compound was prepared as an orange oil in 79.60% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and cyclohexylmethyl bromide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:9]([NH2:11])=[O:10])=[N:4][C:5]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)c1nc(Cl)ccc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of 3-amino-6-chloropyridine-2-carboxylic acid amide (2.57 g, 15 mmol) in dioxane (200 ml) and water (50 ml) was added 4-fluorophenylboronic acid (2.1 g, 15 mmol), K2CO3 (6.2 g, 45 mmol), and tetrakis(triphenylphosphine) palladium(0) (860 mg, 0.75 mmol). The mixture was heated at reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated to a small volume, filtrated and washed with water to yield a crude product. The residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane, in a volume ratio of 1:80, yielding the title compound (2.9 g, yield 85%) as a white solid. The mass spectrum characterising data was as follows: MS (m/z): 232 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:12](=[O:14])[NH:13][C:9]=2[C:8]2[O:7][CH:6]=[CH:5][C:4]=2[C:3]=1[F:23].[CH2:24]([C:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26].C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCCCCC>[CH2:24]([C:27]1([S:30]([IH:21][C:18]2[CH:19]=[CH:20][C:15]([N:11]3[C:10]4[C:2]([F:1])=[C:3]([F:23])[C:4]5[CH:5]=[CH:6][O:7][C:8]=5[C:9]=4[NH:13][C:12]3=[O:14])=[C:16]([F:22])[CH:17]=2)(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: O=c1[nH]c2c3occc3c(F)c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCC1(S(=O)(=O)[IH]c2ccc(-n3c(=O)[nH]c4c5occc5c(F)c(F)c43)c(F)c2)CC1
Temperature: 30 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
TEA (02611 g, 2.581 mmol) was added to a solution of 4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (I-32a: 0.37 g, 0.8604 mmol) in dry DCM (20 mL) at 0° C. This was followed by the addition of 1-allyl-cyclopropanesulfonyl chloride (0.229 g, 1.89 mmol) and catalytic amount of DMAP (10 mg). The reaction mass was stirred for 12 hours at 20-40° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 0.228 g of the product (46% yield). 1H NMR (CDCl3, 300 MHz): δ 7.71 (dd, 3H), 7.30 (t, 1H), 7.00 (s, 1H), 5.56-5.57 (m, 1H), 4.90 (t, 2H), 2.70-2.80 (q, 2H), 1.90-2.05 (m, 2H), 1.10-1.19 (m, 2H). LCMS: 98.85%, m/z=574.4 (M+1). HPLC: 97.1%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2Cl)nc1-c1ccc(C)cc1
Yield: 81.5 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 2-chlorophenylboronic acid (141 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 40 min. The reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 100 mg (81%) of the title compound. ESI/APCI(+): 409 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=CC=1>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:27]=[N:26][CH:25]=2)=[N:6][CH:7]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Brc1ccc(-c2cnco2)nc1

Procedure:
To a stirred suspension of 5-bromopicolinaldehyde (0.412 g, 2.215 mmol, Tetrahedron Letters 2008, 64, 3794-3801) and potassium carbonate (0.3358 g, 2.43 mmol, Rankem) in MeOH (20 mL) was added toluenesulphonylmethyl isocyanide (0.4757 g, 2.43 mmol). The reaction mixture was heated to reflux for about 4 h. The reaction mixture diluted with water (100 mL) and the product was extracted with EtOAc (2×75 mL). The combined organic layers were washed successively with water (2×50 mL) and brine (1×50 mL), dried over sodium sulphate and evaporated to dryness. The crude material obtained was purified by silica gel column chromatography eluted with 10% EtOAC in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 5-(5-bromopyridin-2-yl)oxazole as an off white solid 0.35 g (70.2%), 1H NMR (400 MHz, DMSO): δ 8.7 (d, J=2.4 Hz, 1H), 8.57 (s, 1H), 8.2 (dd, J=8.4 Hz, 1H), 7.8 (s, 1H), 7.7 (d, J=8.8 Hz, 1H), MS m/z: 226 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[I:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][C:53]=1[CH3:54])[NH2:50]>CN(C=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:50][C:49]1[CH:51]=[CH:52][C:53]([CH3:54])=[C:47]([I:46])[CH:48]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1I
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)benzoic acid 3 (2.64 mmol, 500 mg), TBTU (2.77 mmol, 891 mg) and DIPEA (5.29 mmol, 0.873 mL) in DMF (4 mL) was stirred at 50° C. for 15 min. 3-iodo-4-methylaniline (2.77 mmol, 647 mg) was added and stirred overnight at 50° C. Quenched in citric acid solution and extracted with ethyl acetate. Organic layer was washed with brine, dried and evaporated. Purification with chromatography (30% ethyl acetate in heptane) gave 3-(2-cyanopropan-2-yl)-N-(3-iodo-4-methylphenyl)benzamide 111 (861 mg, 81%). NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.42 (s, 3H), 7.23 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2 Hz and 7.4 Hz, 1H), 7.58 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.71 (dq, J=7.8 Hz and 1.2 Hz), 7.76 (m, 1H), 7.78 (m, 1H), 7.96 (t, J=1.6 Hz, 1H), 8.11 (d, J=2.3 Hz, 1H).
Reaction SMILES: O[C:2]1[CH:7]=C[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)[NH:33]C(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=CC=CN=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[N:33]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Brc1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3ccccn3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.17 mmol) (Example 82) was coupled with 2-bromopyridine (25 mg, 0.17 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-5-(2-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 42 mg, 80%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][C:7]2=[O:18])(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.O>[CH2:14]([C:9]1[NH:10][C:11]2[C:6]([C:7](=[O:18])[N:8]=1)=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:13][CH:12]=2)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(=O)c2cc(C(C)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a suspension of 0.102 g of 6-acetyl-2-butyl-4(1H)-quinazolinone in 10.0 ml of ethanol is added 0,015 g of sodium borohydride. The reaction mixture is stirred for 1.5 hours at room temperature and then diluted with 50 ml of water. The aqueous layer is extracted with 5:1 chloroform-methanol and the combined organics dried over magnesium sulfate, filtered and concentrated in vacuo to yield 0.103 g of the desired product. CI MASS SPEC 247(MH+).
Reaction SMILES: [N+:1]([O-])([O-:3])=[O:2].[K+].[OH:6][C:7]1[C:8]([OH:24])=[N:9][C:10]2[CH:11]=[CH:12][C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:14]=3[C:15]=2[N:16]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:8]([OH:24])=[N:9][C:10]2[CH:11]=[C:12]([N+:1]([O-:3])=[O:2])[C:13]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:14]=3[C:15]=2[N:16]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=[N+]([O-])c1cccc2ccc3nc(O)c(O)nc3c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c([N+](=O)[O-])cccc12
Temperature: 25 °C

Procedure:
Finely powdered potassium nitrate (81 mg, 0.8 mmol) was added during a few minutes to a stirred solution of 2,3-dihydroxy-10-nitrobenzo(f)quinoxaline (0.21 g, 0.B mmol) in 3 ml of conc. sulfuric acid at 0° C. After stirring over night at room temperature, the solution was poured into 50 ml of ice/water. The yellow precipitate was isolated, washed with water, dried and recrystallized from 96% ethanol affording 0.12 g (50%) of the dinitro compound, m.p.> 300° C., IR (KBr): 700 cm-1 (C=0),1H-NMR (DMSO-d6): 7.72 (t,J=8 Hz,1H,H-8), 8.10 (dd,J7-8 =8Hz,J7-91Hz, 1H, H-7), 8.23 (s,1H,H-5), 8.55 (dd,J9-8 =8 Hz, J9-7 =1Hz, 1H,H-9), 12.9 (broad s, 1H, OH, only one exchangeable proton could be seen).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[Mg].II.BrC(Br)(CC)CC.[C:18]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([OH:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCO1
Reactant: BrCCCCCBr
Agent: CCC(Br)(Br)CC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OCCCCC1(O)CCCCC1
Yield: 73.6 %

Procedure:
A solution of 1,5-dibromopentane (5 gms, 23.15 mmol) in dry THF (10 ml) was added slowly to a suspension of Magnesium turning (2.8 gms, 112 mmole) in dry THF (50 ml) and catalytic amount of iodine under nitrogen atmosphere. After the addition of about 3 ml of dibromopentane solution in THF, Grignard reaction was initiated. The addition was continued maintaining a gentle reflux. The mixture was refluxed for 16 hours to complete the formation of the Grignard reagent. To the reaction mixture was added a solution of a solution of δ-valerolactone (2.13 gms, 21.3 mmol) in dry THF (50 ml). The resulting mixture was refluxed for 6 hours under nitrogen and then quenched by addition of saturated solution of ammonium chloride at 0° C. The product was extracted in ethylacetate. Organic layer was washed with water, brine and dried over anh. Na2SO4. Drying agent was filtered off and the solvent was removed under vacuum to give 2.7 gms of diol (8), which was used without any further purification in the next step.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH2:21][OH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O>ClCCl.C(N(CC)CC)C>[O:22]([CH2:21][CH:9]1[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(CN2CCN(Cc3ccccc3)C(COc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 6 g portion of 1,4-bis(phenylmethyl)-2-piperazinemethanol was dissolved in 90 ml of dichloromethane together with 4.26 ml of triethylamine and then cooled to 0°-5° C. A 2.04 ml portion of methanesulfonyl chloride was added and the mixture was allowed to warm to room temperature over 2 hours. The mixture was washed with ice cold sodium bicarbonate solution, followed twice with ice water, dried, filtered and evaporated. The residue was dissolved in dimethylformamide and added to a solution of 2.07 g of sodium phenol and 1.02 g of 50% sodium hydride in 30 ml of dimethylformamide under argon. This mixture was stirred for 48 hours, water was added and the mixture extracted twice with ether. The extracts were combined, washed with water, dried, filtered and evaporated, giving a gum which was crystallized from methanol with refrigeration, giving 4.1 g of 3-phenoxymethyl-1,4-bis(phenylmethyl)piperazine.