Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>O.C(OCC)(=O)C>[S:14]([N:7]1[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1cnc[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cncc2CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To an ice cold solution of 0.08 mole of sodium bicarbonate in 40 ml of water is added 0.02 mole of imidazol-5-ylmethanol hydrochloride followed by a solution of 0.025 mole of tosylchloride in 30 ml of ethyl acetate. The reaction mixture is stirred at room temperature for 5 hours. The organic phase is separated, washed with sodium bicarbonate, and dried over magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate to afford 1-tosylimidazol-5-ylmethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1>[Pd].CO.O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c(-c3ccccc3)[nH]c3ccccc23)CCNC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: c1ccc(-c2[nH]c3ccccc3c2C2CCNCC2)cc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
3-(1,2,3,6-Tetrahydropyridin-4-yl)-2-phenyl-1H-indole (25 g, 91 mmol), palladium on carbon (10% w/w, 2.5 g) and NH4HCO2 (57 g, 0.72 mol) were refluxed in MeOH (300 ml) for 8 h. Palladium on carbon (10% w/w, 1.25 g) and NH4HCO2 (29 g, 0.36 mol) were added, and refluxing continued for 8 h. The mixture was cooled, filtered, and evaporated to give a white solid. This was suspended in H2O (1 l) and 1M NaOH (100 ml), and the mixture extracted with CH2Cl2 (5×150 ml). The combined organic layers were washed with water and brine, dried, and evaporated in vacuo to give a white solid, which was recrystallised from MeOH (300 ml) and H2O (100 ml) to give the title compound (19 g, 75%) as white crystals, mp 187-188° C. Oxalate salt, white crystals, mp 209-211° C. (from EtOH). Found C, 69.09; H, 6.65; N, 7.52. C19H20N2. C2H2O4 requires C, 68.84; H, 6.05; N, 7.65%; δH (360 MHz, d6-DMSO) 1.80 (2H, d, J 13, NCH2CHAHB), 2.30-2.50 (2H, m, NCH2CHAHB), 2.91 (2H, t, J 12, NCHAHB), 3.10-3.20 (1H, m, CH2CH), 3.32 (2H, d, J 12, NCHAHB), 6.98 (1H, t, J 7, indole-H), 7.08 (1H, t, J 7, indole-H), 7.20-7.50 (6H, m, ArH), 7.88 (1H, d, J 7, ArH), 11.3 (1H, br s, indole NH); m/z (ES+) 277 (M++H).
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[CH3:5][NH2:6].[OH:7][C@H:8]([C@H:11]([CH3:16])[CH2:12]/[CH:13]=[CH:14]/[CH3:15])[CH:9]=O.O>CO>[C:1]([CH:9]([NH:6][CH3:5])[C@H:8]([OH:7])[C@H:11]([CH3:16])[CH2:12]/[CH:13]=[CH:14]/[CH3:15])#[N:2]
Reactant: CN
Reactant: [C-]#N
Reactant: C/C=C/C[C@@H](C)[C@@H](O)C=O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: C/C=C/C[C@@H](C)[C@@H](O)C(C#N)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.52 g (7.9 mMol) KCN and 0.54 g (7.9 mMol) methylamine hydrochloride are added with stirring at 20° C. to 1.1 g (7.7 mMol) of (2R,3R,5E)-2-hydroxy-3-methyl-5-hepten-1-aldehyde dissolved in 50 ml methanol. After addition of 7.5 ml water the reaction mixture is stirred for a further two hours at room temperature and then concentrated to 1/2 volume on a rotary evaporator at a water-bath temperature of maximally 40° C. The obtained solution is shaken with 300 ml methylene chloride and 200 ml water and the separated organic phase is shaken with a further 100 ml water. The aqueous phases are extracted one after the other using 2×100 ml methylene chloride, the methylene chloride fractions are combined with the first organic extract, and the whole is dried over sodium sulfate, filtered through a G3 -frit and evaporated to yield the title compound as a diastereomeric mixture. This is used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:16])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH2:17]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[S:22])[CH2:18][CH3:19]>CC(C)=O>[ClH:16].[CH2:1]([O:3][C:4]([C:6]1[C:7]([S:22][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[N:20][CH2:17][CH2:18][CH3:19])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCCNC(=S)NCCC
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Solvent: CC(C)=O
Product: CCCN=C(NCCC)Sc1nc2ccccc2nc1C(=O)OCC
Product: Cl

Procedure:
2-Chloro-3-quinoxalinecarboxylic acid ethyl ester (3.551 g., 0.015 mole) and 2.405 g. (0.015 mole) of 1,3-di-n-propylthiourea were dissolved in acetone and heated at reflux for 11/2 hours. The solution was concentrated to a volume of 50 ml. and cooled. A small amount of solid was removed by filtration. The filtrate was further concentrated to a volume of 25 ml. and ether was added to turbidity. After the reaction mixture had been cooled the yellow solid was collected by filtration to give 2.77 g. (46.6%) of the product, m.p. 129°-130° C.
Reaction SMILES: [C:1]1(N=C=O)[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.C1(N=C=O)C=CC=C([N:19]=[C:20]=[O:21])C=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][C:27]=1N=C=O>>[CH:27]1[C:26]([CH2:25][C:1]2[CH:2]=[CH:3][C:4]([N:7]=[C:8]=[O:9])=[CH:5][CH:6]=2)=[CH:31][CH:30]=[C:29]([N:32]=[C:33]=[O:34])[CH:28]=1.[N-:19]=[C:20]=[O:21]
Reactant: O=C=Nc1ccc(N=C=O)cc1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: O=C=Nc1cccc(N=C=O)c1
Product: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Product: [N-]=C=O

Procedure:
The polyether segment is reacted with a diisocyanate, e.g., p-phenylene diisocyanate, m-phenylene diisocyanate, 2,4-toluene diisocyanate and isomers thereof, methylenebis(phenyl isocyanate), methylenebis(chlorophenyl isocyanate), and methylenebis(tolyl isocyanate) to produce an isocyanate-terminated prepolymer or oligomer. The toluene diisocyanates are preferred.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1Br.[C:13]([Cu])#[N:14].CCOC(C)=O.[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:13]#[N:14]
Reactant: COC(=O)c1cccc(Cl)c1Br
Reactant: N#C[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cl)c1C#N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-chlorobenzoic acid methyl ester (3.86 mmol) in 4 mL DMF was added CuCN (4.24 mmol) and the reaction mixture was heated to 90° C. overnight. After cooling to 10° C., 10 mL EtOAc and 3 mL 1M NaOH solution were added and stirring was continued at RT for 30 min. The aq. phase was separated and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by preparative LC-MS (method L) gives the desired product as white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[O:12][CH:9]1[CH:10]=[CH2:11]>C1COCC1.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>[OH:12][CH2:8][CH:9]=[CH:10][CH2:11][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][CH2:8][CH:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:10]=[CH2:11]
Reactant: Oc1ccccc1
Reactant: C=CC1CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(CO)Oc1ccccc1
Product: OCC=CCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Tetrakis(triphenylphosphine)palladium (0.4 g, 0.35 mmol) and phenol were dissolved in 70 mL THF and the solution was cooled to 0° C. Butadiene monoxide (5.5 mL, 50 mmol) was then added, and the reaction was allowed to warm to room temperature. After 2 hours at room temperature, GLC analysis indicated that phenol was no longer present, and that two products were obtained in a 1:4 ratio (1-hydroxy-4-phenoxy-but-2-ene: 4-hydroxy-3-phenoxy-but-1-ene). The solvent and excess butadiene monoxide were removed at reduced pressure, and the residue was chromatographed on silica gel (ether:hexane; 1:1 eluant) giving pure samples of each product in a combined yield of 91%.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:17]=1[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[F:27][C:23]1[CH:22]=[C:21]([C:18]2[C:17]([C:28]3[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:1](=[O:3])[CH3:2])(=[O:36])=[O:35])=[CH:32][CH:33]=3)=[C:16]([CH3:15])[O:20][N:19]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)noc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Acetic anhydride (1.01 g, 9.39 mmol) and triethylamine (0.401 g, 3.97 mmol) were added to a solution of 4-[5-methyl-3-(3-fluorophenyl)isoxazol-4-yl]benzenesulfonamide (1.10 g, 3.31 mmol) and N,N-dimethylpyridine (0.202 g) in dry tetrahydrofuran. After stirring for 18 hours at room temperature, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid and brine, dried over anhydrous MgSO4 and concentrated to afford 1.0 g (81%) of the desired product as a crystalline product: mp 144-145° C. 1H NMR (CDCl3) 8.00 (d, 2H, J=7.3 Hz), 7.30-7.27 (m, 4H), 7.10-7.06 (m, 3H), 2.46 (s, 3H), 1.99 (s, 3H). Anal. Calc'd for C18H15FN2O4S: C, 57.75; H, 4.04; N, 7.48. Found: C, 57.84; H, 4.06; N, 7.49.
Reaction SMILES: [O:1]1[C:5](=[O:6])[C:4](=O)[C:3]2[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:2]1=2.Cl.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:26](O)[CH3:27]>>[C:18]1([N:24]2[C:2]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[CH2:10][CH2:9][CH2:8][C:3]=3[C:4]([C:5]([O:1][CH2:26][CH3:27])=[O:6])=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1OC2=C(CCCc3ccccc32)C1=O
Reactant: NNc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1nn(-c2ccccc2)c2c1CCCc1ccccc1-2

Procedure:
A mixture of 25 parts of 5,6-dihydro-4H-benzo-[6,7]cyclohepta[1,2-b]furan-2,3-dione, 21 parts of phenylhydrazine hydrochloride and 400 parts of absolute ethanol are refluxed for 6 hours. The ethanol is then removed under reduced pressure and the resulting residue is partitioned between benzene and water with sufficient potassium carbonate being added to make the mixture alkaline. The organic layer is then separated and washed twice with water before it is dried over potassium carbonate and the solvent is evaporated under reduced pressure. The resulting residue is recrystallized from hexane to give ethyl 1-phenyl-1,4,5,6-tetrahydrobenzo-[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate melting at about 110°-111°C.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=1.[C:16]([O-])(O)=O.[Na+]>CO>[NH2:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: Nc1cccc(C(=O)O)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(N)n1

Procedure:
H2SO4 (3.0 eq.) was added to a suspension of 6-aminopyridine-2-carboxylic acid in MeOH (0.3 M). The reaction mixture was heated to reflux for 20 h. After cooling down, the solvent was reduced in vacuo and the residue was added to cooled sat. aq. NaHCO3. The aqueous phase was extracted with DCM (2×) and the combined organic extracts were washed with brine and dried (Na2SO4). Evaporation of the solvent yielded the title compound as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 300K) δ 7.50 (1H, t, J=7.8 Hz), 7.18 (1H, d, J=7.3 Hz), 6.65 (1H, d, J=8.3 Hz), 6.28 (2H, bs), 3.79 (3H, s). MS (ES+) C7H8N2O2 requires: 152, found: 153 (M+H)+.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[O:32]=[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(4-methylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 11, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7](NC3C=CC(Br)=CC=3)[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].CN(C)C=[O:24]>>[N:6]1[CH:3]=[CH:2][CH:18]=[CH:17][C:5]=1[C:4]([NH:8][CH3:7])=[O:24]
Reactant: CN(C)C=O
Reactant: Nc1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)c1ccccn1

Procedure:
To a solution of ((5-aminobenzimidazol-2-yl)(4-bromophenylamine (1 eq) in N,N-dimethylformamide was added sodium hydride (2 eq) and the mixture was microwaved for 8 mins at 220° C. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried with sodium sulfate and concentrated. Preparative chromatography yielded [4-({2-[(4-bromophenyl)amino}benzimidazol-5-yl}amino)(2-pyridyl_-N-methylcarboxamide. MS: MH+=437.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:42]=[CH:41][C:19]([O:20][C:21]2[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:35][CH2:34][CH:33]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([F:43])[CH:17]=1.CCCCCC>C(#N)C.C(OCC)C>[F:43][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:42]=[CH:41][C:19]=1[O:20][C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:29])[CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCCC4)CC3)ncn2)c(F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2cc(NC(=O)N3CCC(N4CCCC4)CC3)ncn2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
2-Phenylacetyl chloride (0.053 ml) was dissolved in acetonitrile (4 ml) under a nitrogen atmosphere, and then potassium thiocyanate (77.7 mg) was added thereto at 60° C., followed by stirring at the same temperature for 2 hrs. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added a solution of 4-(pyrrolidin-1-yl)piperidin-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (49.0 mg) in acetonitrile (5 ml) under a nitrogen atmosphere, followed by stirring at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1). The resultant crude product was purified again by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=19:1). Fractions containing the target compound were concentrated to give a residue, which was suspended in diethyl ether (0.5 ml)-hexane (1.0 ml). The solid was filtered off and dried under aeration to provide the titled compound (8.1 mg, 11.5%) as a white solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([OH:17])=O)[N:6]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[NH:23][C:24]([C:26]1[C:34]2[NH:33][C:32]([NH2:35])=[N:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:20]1[CH:21]=[CH:22][N:18]=[C:19]1[NH:23][C:24]([C:26]1[C:34]2[N:33]=[C:32]([NH:35][C:15]([C:7]3[N:6]=[C:5]([CH2:4][CH2:3][S:2][CH3:1])[C:14]4[C:9]([CH:8]=3)=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:17])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: CSCCc1nc(C(=O)O)cc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSCCc1nc(C(=O)Nc2nc3c(C(=O)Nc4ncc[nH]4)cccc3[nH]2)cc2ccccc12
Yield: 67.1 %

Procedure:
42.4 mg (0.171 mmol) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid was reacted with 34 mg (0.14 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 114 mg (0.3 mmol) of HBTU and 0.106 mL (0.6 mmol) of DIEA in 0.8 mL of DMF stirring at 85° C. for 3 h according to the general procedure A. 44.3 mg (55%) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was obtained. LCMS: 472 (M+1)+.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[N:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cncc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 15.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.10 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1 N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated and purified on silica gel (0-45% ethyl acetate/hexanes) to give the desired product (0.020 g, 16%). LCMS calculated for C14H12FN6OS (M+H)+: m/z=331.1. Found: 331.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([SH:24])[N:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([S:24][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:12]([Cl:15])([Cl:14])[Cl:13])[N:18]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)nc(SSc2ccc([N+](=O)[O-])cc2C(Cl)(Cl)Cl)n1
Reaction time: 12 h
Yield: 91.4 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride, dissolved in 500 ml of glacial acetic acid, are mixed with 28 g of 4,6-dimethyl-2-mercaptopyrimidine and 16.4 g of sodium acetate at 20° C. After 12 hours, the precipitate is filtered off, washed with water and dried over potassium hydroxide. 75 g (91% of theory) of 4,6-dimethylpyrimidin-2-yl-dithio-(4-nitro-2-trichloromethylbenzene), of melting point 151° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH2:5][OH:6].[H][H]>CO.[Pd]>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][OH:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CO)ccc1N
Yield: 91.1 %

Procedure:
A solution of 3-methyl-4-nitrobenzyl alcohol (Aldrich; 2.000 g; 12.0 mmol) in MeOH (90 ml) is passed through the H-Cube flow hydrogenator fitted with a 10 mol % Pd/C catalyst cartridge (30×4 mm) heated to 25° C. with the full hydrogen option enabled. The flow rate is set at 1 mL/min. Solvent was removed to give the title compound (1.50 g, 91.4%) without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[C:3]([O:27][CH2:28][C:29]#[N:30])[CH:4]=[CH:5]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(-c4ccccc4)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 70 °C
Reaction time: 22 h
Yield: 48.1 %

Procedure:
Following the procedure described in Step 1 of Example 1, 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.480 g, 1.04 mmol) was coupled to phenylboronic acid (0.448 g, 3.67 mmol) using [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (0.0918 g, 0.112 mmol) in presence of potassium carbonate (0.290 g, 2.10 mmol) in dioxane (10 mL) and water (1.0 mL). The reaction mixture was stirred at 70° C. for 22 hours. Purification by flash chromatography (Biotage apparatus) using 7.5-10% tert-butyl methyl ether in hexane furnished the title compound (0.230 g). 1HNMR (300 MHz, DMSO-d6): δ8.5 (s, 1H), 8.3 (d, 1H, J=9.2 Hz), 8.05 (d, 1H, J=7.7 Hz), 7.7-7.85 (m, 3H), 7.35-7.6 (m, 9H), 5.25 (s, 2H), 2.75 (t, 2H, J=7.7 Hz), 1.5-1.6 (m, 2H), 1.1-1.3 (m, 2H), and 0.75 ppm (t, 3H, J=7.7 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18](Cl)=[O:19])=[CH:14][CH:13]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(Cl)Cl>[CH2:24]([N:26]([CH2:27][CH3:28])[C:18](=[O:19])[CH:17]([O:16][C:15]1[CH:22]=[CH:23][C:12]([O:11][C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:13][CH:14]=1)[CH3:21])[CH3:25]
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)Cl
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound can be prepared by interaction of 2-[4-(2-quinoxalinyloxy)phenoxy]propionic acid with thionyl chloride in a suitable solvent such as chlorobutane. Add a solution of 3.3 g (0.01 mole) 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 30 cc methylene chloride to a cold (5° C.) solution of 1.8 g (0.025 mole) diethylamine in 30 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry over magnesium sulfate. Remove the methylene chloride under vacuum to yield N,N-diethyl-2-[4-(quinoxalinyloxy)phenoxy]propanamide.