Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH3:8][S:9]([O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:8][S:9]([O:12][C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([C:24]([F:27])([F:25])[F:26])=[CH:19][CH:20]=2)[N:15]([CH3:5])[CH:14]=1)(=[O:11])=[O:10]
Reactant: COS(=O)(=O)OC
Reactant: CS(=O)(=O)Oc1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
Dimethyl sulphate (26.1ml) was added to a stirred suspension of 4-hydroxy-7-trifluoromethylquinol-3-yl methanesulphonate (7.19 g) and potassium carbonate (75.5 g) in dry 2-butanone (350 ml) and the resultant mixture was heated under reflux for 5 hours. The solvent was removed by distillation and the resultant residue was extracted with dichloromethane (600 ml then 400 ml). The combined extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (75:1) followed by flash chromatography on a silica gel column eluted with ethyl acetate and crystallisation from industrial methylated spirit (150 ml) to give the novel compound 1-methyl-4-oxo-7-trifluoromethyl-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 218°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([NH:21][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of p-Nitrobenzenesulfonylchloride (274 g, 1.2 eq) in DCM (1 l), was added to a solution of benzylamine (500 g, 1 eq) and triethylamine (469 ml, 1.5 eq) in DCM (1 l) at 4° C. in small portions and then stirred for 1 h. Afterwards the mixture was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was washed with a mixture of DCM/PE (1/1) at 4° C., filtered and dried in vacuo to give N-Benzyl-4-nitrobenzenesulfonamide. Yield 90%.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:11]([N:18]1[C:22]2[C:23](=[O:34])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1S(C)(=O)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>O>[CH2:11]([N:18]1[C:22]2[C:23](=[O:34])[N:24]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)c1nc2ccn(Cc3ccccc3)c(=O)c2n1Cc1ccccc1
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(ccn1Cc1ccccc1)nc(N1CCNCC1)n2Cc1ccccc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 5.5 %

Procedure:
660 mg (11 mmol) of glacial acetic acid were added dropwise to 860 mg (10 mmol) of piperazine with cooling, then 180 mg of 3,5-dibenzyl-2-methanesulphonyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one (crude product from Example 3 h) were added and the mixture was stirred for 24 hours at 150° C. After cooling approx. 10 ml of water were added, the mixture was made alkaline with concentrated ammonia solution and the mixture was extracted three times with 5 ml of dichloromethane. The extracts were dried over sodium sulphate and concentrated by evaporation. The crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 20–60% ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:16](O)[CH2:17][CH3:18]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCCO
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenyl acetic acid (9.12 g, 0.06 mol), n-propanol (40 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours, then evaporated in vacuo. The residue was extracted with ethyl acetate (200 mL), washed with 10% Na2CO3, then water dried (MgSO4), and evaporated in vacuo to give n-propyl 4-hydroxyphenylacetate as an oil. A solution of n-propyl 4-hydroxyphenylacetate (5.8 g, 0.03 mol) in epichlorohydrin (50 mL) was refluxed in the presence of DBU (2 mL, 0.014 mol for 2 hours. After the excess epichlorohydrin was removed, the residue was refluxed with isopropylamine (20 mL, 0.23 mol in n-propanol (50 mL), for 4 hours, then was evaporated in vacuo. The residue was crystallized from n-hexane to yield 3.8 g (41%) of n-propyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, melting at 61°-62° C. and having the structural formula: ##STR29##
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:17]=[C:16]([OH:18])[NH:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:17]=[C:16]([OH:18])[NH:15][N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2cc(O)[nH]n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Oc1cc([C@@H]2CCNC2)n[nH]1
Reaction time: 48 h

Procedure:
To a solution of (R)-3-(5-hydroxy-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (44 mg, 0.17 mmol) in CH2Cl2 (1 mL) was added HCl in dioxane (0.2 mL, 4.0 M). The reaction mixture was stirred for 48 h. Solvent was removed at reduced pressure to afford crude (R)-5-pyrrolidin-3-yl-2H-pyrazol-3-ol as a white solid. The material was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Oc1ccc(S)cc1
Product: O=C1CCc2cc(OCCCCSc3ccc(O)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 4-hydroxy-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]2[C:4](=[CH:5][N:6]([CH:13]3[CH2:14][CH2:15]3)[N:7]=2)[CH:3]=1
Reactant: OCc1cc(Cl)cc2cn(C3CC3)nc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(5-Chloro-2-cyclopropyl-2H-indazol-7-yl)methanol (0.39 g, 1.75 mmol) and triethylamine (0.73 mL, 5.25 mmol) were combined in dimethyl sulfoxide (4 mL) and cooled to 0° C. The reaction was treated with sulfur trioxide pyridine complex (0.87 g, 5.25 mmol) in dimethyl sulfoxide (2 mL), stirred at 0° C. for 5 min, and at room temperature for 20 min. The reaction was poured into ice water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with 10% acetic acid (2×), water (2×), saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) gave 298 mg (77%) as a yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 10.52 (s, 1H), 8.05 (s, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 3.96-4.03 (m, 1H), 1.35-1.40 (m, 2H), 1.16-1.23 (m, 2H). Mass spec.: 221.30 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[S:12][CH2:13][CH2:14][N:15]=1.[H-].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]([C:11]1[S:12][CH2:13][CH2:14][N:15]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(CNC2=NCCS2)c1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cccc(C)c1C)C1=NCCS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Under a dry nitrogen atmosphere, a solution of 0.25 gram (0.0011 mole) of ((2,3-dimethylphenyl)methyl)-1,3-thiazolin-2-ylamine dissolved in 10 mL of THF was added to a stirred suspension of 0.08 gram (0.0012 mole) of sodium hydride (60% suspension in oil). The mixture was stirred for 30 minutes, at which time a solution of 0.11 mL (0.0014 mole) of methyl chloroformate in 5 mL of THF was added slowly. The reaction mixture stirred at ambient temperature for about 18 hours. The reaction mixture was heated to 60° C. where it stirred for one hour. The reaction mixture was diluted with 25 mL of brine, then extracted with two 25 mL portions of ethyl acetate. The extracts were combined, washed with 25 mL of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to leave a solid residue. Analysis of the residue by TLC indicated that two compounds were present. The residue was purified by column chromatography on silica gel, eluting with hexanes:methylene chloride (1:1). The appropriate fractions were combined and concentrated under reduced pressure to yield 0.05 gram of methyl 2-(1-aza-2-(2,3-dimethylphenyl)ethylidene)-1,3-thiazolidine-3-carboxylate (Compound C53) and 0.14 gram of N-((2,3-dimethylphenyl)methyl)methoxy-N-(1,3-thiazolin-2-yl)carboxamide (Compound D5). The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C[O-].[Na+].[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH2:17][CH2:18]Br)=[C:13]([CH2:22][CH2:23][CH3:24])[C:12]=1[OH:25])(=[O:10])[CH3:9]>>[C:8]([C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][CH2:17][CH2:18][S:1][CH2:2][CH2:3][OH:4])=[C:13]([CH2:22][CH2:23][CH3:24])[C:12]=1[OH:25])(=[O:10])[CH3:9]
Reactant: OCCS
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: C[O-]
Agent: [Na+]
Product: CCCc1c(OCCCSCCO)ccc(C(C)=O)c1O

Procedure:
4.68 g. (60 mMole) 2-mercaptoethanol are stirred for 10 minutes at ambient temperature with 60 ml. 1 M sodium methylate solution. Subsequently, 9.39 g. 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl bromide are added thereto and the reaction mixture is boiled under reflux for 5 hours. The reaction mixture is thereafter evaporated and the residue mixed with water and ethyl acetate. The ethyl acetate phase is successively shaken with 2 M aqueous sodium hydroxide solution and with 2 M hydrochloric acid and then dried and evaporated. After recrystallising the residue from diethyl ether/ligroin, there are obtained 6.4 g. (68% of theory) of the title compound; m.p. 72-74° C.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[C:13]([N:17]1[C:22](=[O:23])[C:21]([Cl:24])=[C:20]([SH:25])[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([N:17]1[C:22](=[O:23])[C:21]([Cl:24])=[C:20]([S:25][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:3]=[C:2]([Cl:12])[Cl:1])=[CH:5][CH:6]=2)[CH:19]=[N:18]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: ClC(Cl)=Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(C=C(Cl)Cl)cc2)c(Cl)c1=O

Procedure:
1.2 g of 4-(2,2-dichloroethenyl)-benzyl bromide and 0.8 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.7 g of potassium carbonate in 10 cc of dimethylformamide.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>CN(C)C=O.CO.[Cu]>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
4 g of a potassium salt of 5-hydroxy-2-methylpyridine was suspended in 10 ml of dimethylformamide, and 6.15 g of p-bromobenzotrifluoride and 500 mg of a copper powder were added to the suspension, followed by stirring in a nitrogen stream at 125° C. for 18 hours to effect the reaction. The reaction mixture was allowed to cool, diluted with 50 ml of methanol and then filtered. The filtrate was immediately dried to a solid, and 150 ml of chloroform and 100 ml of water were added to the residue. The resulting mixture was adjusted to a pH of 9.5 with 5 N sodium hydroxide and any insoluble matter again separated by filtration. The chloroform layer was dried with anhydrous sodium sulfate and immediately concentrated to dryness to obtain 5.6 g of oily 5-(p-trifluoromethylphenoxy)-2-methylpyridine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:7]=2[CH:32]=1.C1(=O)[NH:37]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C>[NH2:37][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[NH:8][C:7]=2[CH:32]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCN(CCC)CCCCc1nc2ccc(CCl)cc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCc1nc2ccc(CN)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
The compound (113 mg) obtained in Example 2-3 was dissolved in DMF (2.0 ml) and added with potassium phthalimide (69.0 mg) and the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with water. After extraction with chloroform, the organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was dried under vacuum, and the dried product was dissolved in a 40% methylamine/methanol solution (1.5 ml), followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with water and a 1 mol/l sodium hydroxide aqueous solution. After extraction with chloroform, the extract was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (39.8 mg) as a brown solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:2][CH2:3][CH3:4].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[C:28]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:7]=1)([CH3:35])[CH3:34])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCCc1ccc(O)cc1OCCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 82.3 %

Procedure:
A mixture of 4-butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol (0.11 g, 0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 5-15% EtOAc/Hex to give a yellow oil (0.12 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=7.6, 1,7 Hz, 2H), 7.45-7.39 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.3, 2.0 Hz, 1H), 4.25-4.17 (m, 4H), 2.97 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.56 (s, 6H), 1.43 (quintet, J=7.7 Hz, 2H), 1.30-1.22 (m, 5H), 0.86 (t, J=7.3 Hz, 3H), MS (ES) m/e 466 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10]N1C2C=CC=CC=2N=N1.[CH3:20][C:21]1[C:29]([CH3:30])=[CH:28][C:24]2[NH:25][N:26]=[N:27][C:23]=2[CH:22]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:27]1[C:23]2[CH:22]=[C:21]([CH3:20])[C:29]([CH3:30])=[CH:28][C:24]=2[N:25]=[N:26]1
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Reactant: Cc1cc2nn[nH]c2cc1C
Product: Cc1cc2nnn(Cc3nc4ccccc4[nH]3)c2cc1C

Procedure:
The same procedure described in the preparation of 1-(1H-benzimidazol-2-ylmethyl)-1H-benzotriazole was used, except that 5,6-dimethylbenzotriazole was used instead of benzotriazole. 1-(1H-benzimidazol-2-ylmethyl)-5,6-dimethyl-1H-benzotriazole was isolated as an intermediate:
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:29]1([P:35](Cl)(Cl)=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.C1CCCCC1>[C:29]1([P:35]2(=[O:36])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][N:21]2[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(NCc2ccccc2)cc1
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: Cc1ccc(N2Cc3ccccc3P2(=O)c2ccccc2)cc1
Temperature: 26 °C
Reaction time: 4 h
Yield: 19.8 %

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (3.9 g, 0.061 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzyl-4-toluidine (5.9 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. The suspension containing the dilithio compound was stirred for 4 hours at 26° C. and then cooled to 0° C. A solution of phenylphosphonic dichloride (6.25 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension and the resulting mixture was stirred for 1.5 hours at 26° C. The reaction was quenched with the rapid addition of 6 ml. of acetic acid. The mixture was concentrated in vacuo and the resulting residue partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, then water, dried over sodium sulfate and concentrated in vacuo to yield a brown-green glass. The brown-green glass was crystallized from ethyl acetate to yield light green plates which were recrystallized from toluene to yield 1-phenyl-2-(4-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.9 g, 20% yield) as white crystals having a melting point of 197°-199° C. and the following analysis:
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:9]2[CH:10]=[C:11]([C:13]([O:15]C)=[O:14])[O:12][C:8]=2[CH:7]=[C:6]([N+:17]([O-:19])=[O:18])[C:5]=1[O:20][CH3:21]>CO.O>[Cl:3][C:4]1[C:9]2[CH:10]=[C:11]([C:13]([OH:15])=[O:14])[O:12][C:8]=2[CH:7]=[C:6]([N+:17]([O-:19])=[O:18])[C:5]=1[O:20][CH3:21]
Reactant: COC(=O)c1cc2c(Cl)c(OC)c([N+](=O)[O-])cc2o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c([N+](=O)[O-])cc2oc(C(=O)O)cc2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
Lithium hydroxide (0.9 g, 21.0 mmol) was added to a stirred suspension of methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate (2.0 g, 7.0 mmol) in methanol-water (3:1) (40 mL). The reaction was allowed to stir for 3 h at room temperature. The reaction was then concentrated under reduced pressure and the resulting residue was dissolved in water and washed with diethyl ether. The aqueous phase was acidified by the addition of 2M aqueous hydrochloric acid then extracted with ethyl acetate. The combined organic extracts were passed through a phase separation cartridge and evaporated to afford a white solid (1.17 g, 61%), which was taken through to the next step with no further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]1[N:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[C:16](=[O:26])[C:15]2=[C:27](Br)[CH:28]=[CH:29][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([Zn]C#N)#[N:40]>CN(C)C=O.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>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]1[N:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[C:16](=[O:26])[C:15]2=[C:27]([C:39]#[N:40])[CH:28]=[CH:29][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(Br)c2c(=O)n1-c1cc(F)cc(F)c1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(C#N)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
In a reactor vessel (S)-tert-butyl (3-(benzyloxy)-1-(5-bromo-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (0.81 g, 1.37 mmol) was dissolved in 32 mL dimethylformamide. Dicyanozinc (0.4 g, 3.49 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.64 g, 0.55 mmol) were added under argon conditions. The reaction was stirred at 120° C. overnight. The crude was filtered through a plug of Celite and washed several times with ethyl acetate. The combinated filtrates were evaporated and washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1 ® Purification System (0% to 40%, hexane-ethyl acetate) to obtain 0.58 g (77% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH3:37])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 4-methylbenzenesulfonylchloride to give 70 mg 5-methyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.55 min [M+1]+663.56, [M−1]−=661.63.