Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.C[Si]([O:9][CH2:10][C:11]#[CH:12])(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@:22]([C:12]#[C:11][CH2:10][OH:9])([OH:26])[C@@H:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C#CCO[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[Mg]Br
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−5° C.) solution of ethylmagnesium bromide (1M in tetrahydrofuran, 130 ml, 130 mmol) in tetrahydrofuran was added O-trimethylsilylpropargyl alcohol slowly. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 2 hours, before cooling to −10° C. To this was then added a solution of (2S)-1-tert-butyloxycarbonyl-2-phenylpiperidin-3-one (Desc. 1; 30 g, 108 mmol) in tetrahydrofuran keeping the temperature below 5° C. The reaction was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (200 ml/200 ml) and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and evaporated to an oil. This oil was dissolved in ethyl acetate (400 ml) and a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 130 ml, 130 mmol) added. After stirring at room temperature for 2 hours, water (200 ml) was added, and the two layers separated. The aqueous phase was further extracted with ethyl acetate (200 ml), the organic layers dried (MgSO4) and evaporated to give the product as an oil (50 g) which was used crude for Description 3. 1H NMR (CDCl3) δ7.53-7.55 (2H, m), 7.19-7.35 (3H, m) 5.56 (1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m) 3.25 (1H, bs), 2.77-2.81 (1H, m) 2.77 (1H, bs), 2.12-2.20 (1H, m) 1.91-1.99 (2H, m), 1.77-1.83 (1H, m), 1.39 (9H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[CH3:19][C:15]1[CH:14]=[C:13](/[C:10](=[N:11]/[OH:12])/[CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(Br)cc2)c2ccccc2C)=N/O)ccn1
Reactant: OB(O)c1cncnc1
Product: Cc1cc(/C(C[C@H](c2ccc(-c3cncnc3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 22, from (E,R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one oxime (example 142, step 1) and pyrimidine-5-boronic acid was prepared the title compound as a white foam, MS (ESI+): m/z=409.3 ([M+H]+).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH2:13]OS(C)(=O)=O)=[CH:11][C:10]([Br:19])=[CH:9][N:8]=1)(=O)=O.[CH3:20][Si:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28][C:27]1=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C>[Br:19][C:10]1[CH:11]=[C:12]2[CH2:13][C:28]3([C:29]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:36])([CH3:20])[CH3:37])[C:27]3=[O:35])[CH2:6][C:7]2=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reactant: CS(=O)(=O)OCc1cc(Br)cnc1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(Br)cnc3C2)c2cccnc21
Reaction time: 20 h

Procedure:
(5-Bromopyridine-2,3-diyl)dimethanediyl dimethanesulfonate (17.0 g, 45.4 mmol) was added to a mixture of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902, 14.0 g, 53.0 mmol) and cesium carbonate (49.0 g, 150 mmol) in ethanol (500 mL) 23° C., and the resulting mixture was stirred for 20 h. The reaction mixture was concentrated then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified via silica gel chromatography (heptane initially, grading to 100% EtOAc) to give the title compound. MS: m/z=448.1 (M+1).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]2[N:5]=1)=O.[CH3:24][N:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1>>[CH3:24][N:25]1[C:29]2[CH:30]=[C:31]([NH:34][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[N:6]4[N:5]=3)[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3NS(C)(=O)=O)n2n1
Reactant: Cn1cnc2ccc(N)cc21
Product: Cn1cnc2ccc(Nc3ncc4ccc(-c5ccccc5NS(C)(=O)=O)n4n3)cc21

Procedure:
Following the synthetic and purification procedures described in Example 1293d, N-[2-(2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (56 mg, 0.16 mmol) was coupled with 3-methyl-3H-benzimidazol-5-ylamine (40 mg, 0.28 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 19 mg (22%) of brown powder; LC/MS: 434 (M+H); HPLC: 95% pure, RT=2.19 min; 1H NMR: (DMSO, δ) 10.01 (s, 1H), 9.92 (s, 1H), 9.33 (s, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 7.93 (d, J=7.7, 1H), 7.80 (m, 1H), 7.77 (d, J=9.0, 1H), 7.71 (d, J=9.0, 1H), 7.55 (t, J=7.8, 1H), 7.29 (d, J=7.9, 1H), 7.09 (d, J=4.8, 1H), 7.03 (d, J=4.8, 1H), 3.84 (s, 3H), 3.01 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:14][CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:14][CH2:15][CH3:16])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCCBr
Reactant: Oc1ccc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc2c(Cl)nccc2c1
Yield: 63.2 %

Procedure:
A mixture of 1-chloroisoquinolin-6-ol (0.898 g, 5 mmol), 1-bromopropane (1.230 g, 10.00 mmol), and K2CO3 (2.073 g, 15.00 mmol) in acetone (20 mL) was refluxed for 16 h. The reaction mixture was filtrated and washed with acetone. the filtrate was concentrated and purified by silica gel chromatography eluting with 10-20% ethyl acetate in hexane to give 700 mg of the product 1-chloro-6-propoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27-8.16 (m, 2H), 7.48 (d, J=5.8 Hz, 1H), 7.31 (dd, J=9.3, 2.5 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 2.02-1.84 (m, 2H), 1.11 (d, J=14.8 Hz, 1H); MS: MS m/z 222.16 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH:7]2[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[H][H]>C(O)C.[Pd]>[CH3:17][O:16][C:5]1[CH:4]=[CH:3][CH:2]=[C:10]2[C:6]=1[CH:7]([CH2:12][C:13](=[O:15])[CH3:14])[NH:8][C:9]2=[O:11]
Reactant: COc1ccc(Br)c2c1C(CC(C)=O)NC2=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc2c1C(CC(C)=O)NC2=O
Yield: 73.4 %

Procedure:
A mixture of 7-bromo-1,3-dihydro-4-methoxy-3-(2-oxopropyl)-2H-isoindol-1-one (5.0 g, described in Example 20) and potassium carbonate (2.5 g) in ethanol (100 ml) is hydrogenated in the presence of 5% palladium on carbon (2.5 g) at atmospheric pressure and room temperature until 1.1 equivalent of hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated. A solution of the residue in chloroform is washed with water, dried and evaporated. The residue is crystallized from dichloromethane-diethyl ether to give the title compound (2.7g): mp 176.5°-177.5° C.; nmr (CDCl3) δ 2.20 (s, 3H), 2.30 (2d, 2H), 3.57 (2d, 2H), 3.87 (s, 3H), 4.85 (2d, 1H), 6.70(s, 1H), 6.97 (t, 1H) and 7.37(d, 2H); and Anal. Calcd for C12H13NO3 : C, 65.74 % H, 5.98% N, 6.39% and Found: C, 65.64% H, 6.09% N, 6.70%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH2:19][C:20](O)=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.ON.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([CH2:19][C:20]([NH:26][OH:25])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(Cc1cc(C(=O)c2ccc(Cl)cc2)sc1-c1ccccc1)NO
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a stirred mixture of 30 mg (0.08 mmol) of 1, 11 mg (0.08 mmol) of N-hydroxybenzotriazole (HOBt), 21 mg (0.11 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl), and 28 mL (0.25 mmol) of 4-methylmorpholine in 5 mL dry CH2Cl2 was added 6 mg (0.08 mmol) of HONH2.HCl at room temperature. The resulting mixture was stirred overnight and washed with 5 mL of H2O. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc) to give 6 mg (20%) of 2 as a white viscous residue that solidified slowly at room temperature: 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.90 (brs, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.68-7.50 (m, 7H), 3.39 (s, 2H); 13C NMR (100 MHz, DMSO-d6) 185.9, 166.3, 148.8, 139.7, 138.6, 137.4, 136.0, 133.0, 132.3, 130.6, 129.2, 129.2, 129.1, 128.9; IR (KBr) cm−1 3305, 3223, 3060, 2921, 1746, 1631, 1436; LREIMS C19H14ClNO3S requires 371.04. Found: 371 ([M+], 9%), 355 (100%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][C:49]=1[CH2:50][O:51][Si](C(C)(C)C)(C)C)[CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH:36]=[CH:37][CH:38]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][C:49]=1[CH2:50][OH:51])[CH2:31][O:32][C:33]1[CH:34]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(O)CCCCc1cccc(OCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(O)CCCCc1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 3(I), by reacting 2 ml of tetrabutylammonium fluoride 1M/THF with 490 mg (0.83 mmol) of 6-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)benzyloxy]phenyl}-2-methylhexan-2-ol in 15 ml of THF, after purification on a silica column (ethyl acetate 90-heptane 10), a yellow oil (m=196 mg; Y=66%) is obtained.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:5].[O:28]1CCCC1.OO.[OH-].[Li+]>O>[OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:3]([CH2:18][CH2:19][C:20]#[CH:21])[C:4]([OH:5])=[O:28]
Reactant: C1CCOC1
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C#CCC[C@@H](C(=O)O)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a stirred solution of 65.0 g (179 mmol) of (4S)-3-{(2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoyl}-4-phenyl-1,3-oxazolidin-2-one from Step B above in 1050 mL of a 20 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 77.0 mL (894 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 395 mL (395 mmol) of a 1.0 M aqueous lithium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 5° C. All volatiles were removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3×200 mL). The aqueous phase was then cooled to 0° C. and acidified with a 6 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×300 mL) and the combined organics were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient to afford the title compound as a colorless gum (32.0 g, 82.0%). 1H NMR (500 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.85 (d, J=8.2, 1H), 3.03-2.97 (m, 1H), 2.29-2.15 (m, 2H), 1.97 (t, J=2.5 Hz, 1H), 1.93-1.82 (m, 1H), 1.62-1.55 (m, 1H). LC-MS: m/z (ES) 201.0 (MH-H2O)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[CH3:25][C:21]1[CH:20]=[C:19]([N:18]([CH2:16][CH3:17])[CH2:26][CH3:27])[CH:24]=[CH:23][C:22]=1[C:11]([C:6]1[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CCN(CC)c1cccc(C)c1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c(C)c1
Temperature: 0 °C
Yield: 77.3 %

Procedure:
A mixture of tetrachlorophthalic anhydride (21.4 g.), N,N-diethyl-m-toluidine (41 g.), aluminum chloride (30 g.) and o-dichlorobenzene (90 ml.) was heated (75°-95° C.) during one to two hours, then diluted with ice-water. The o-dichlorobenzene layer was separated and steam distilled. The residue was heated with dilute sulfuric acid. The mixture was poured onto ice and made alkaline. The resulting oil was heated in concentrated sulfuric acid. Dilution with water and purification of the product with toluene and hexane afforded 2-(2-methyl-4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (IV: Y2 = CH3, Y'4 = (CH3CH2)2N, Z4 = Z"5 = Z"6 = Z7 = Cl) (26 g., m.p. 117° C. with sublimation).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Br:1])[CH:9]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Br)cnn1C
Yield: 81.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.031 g, 0.11 mmol) was treated with 3-acetylphenyl isocyanate (0.019 g, 15.8 μL, 0.11 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 17 (0.038 g, 0.09 mmol, 79%) as a white solid. LCMS m/z (%)=443 (M+H79Br, 99), 466 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.30 (s, 1H), 8.19 (s, 1H), 8.13 (t, J=1.8 Hz, 1H), 7.80 (dd, J=1.4, 8.1 Hz, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[CH:7]=2.[C-:16]#[N:17].[Na+].[C-]#N.[K+]>>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([CH2:2][C:16]#[N:17])[C:4]([CH3:15])=[N:5]2)=[CH:10][CH:9]=1
Reactant: [C-]#N
Reactant: COc1ccc2cc(CCl)c(C)nc2c1
Agent: [K+]
Agent: [Na+]
Product: COc1ccc2cc(CC#N)c(C)nc2c1

Procedure:
Compounds of formula (50), wherein R4 and R5 are as defined in formula (I) and R6 is aryl or heteroaryl, can be prepared as described in Scheme 6. Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be prepared using the procedures described in Synthetic Comm., 17(14):1647-1653 (1987). Ethyl 7-methoxy-2-methyl-3-quinolinecarboxylate can be treated with a reducing agent, such as, but not limited to, lithium aluminum hydride or sodium borohydride, to provide (7-methoxy-2-methyl-3-quinolinyl)methanol. (7-Methoxy-2-methyl-3-quinolinyl)methanol can be treated with a chlorinating reagent, such as, but not limited to, thionyl chloride to provide 3-(chloromethyl)-7-methoxy-2-methylquinoline. 3-(Chloromethyl)-7-methoxy-2-methylquinoline can be treated with sodium cyanide or potassium cyanide to provide (7-methoxy-2-methyl-3-quinolinyl)acetonitrile. (7-Methoxy-2-methyl-3-quinolinyl)acetonitrile can be treated with acid, such as, but not limited to, glacial acetic acid and concentrated sulfuric acid, in water and 1,4-dioxane with heat to provide (7-methoxy-2-methyl-3-quinolinyl)acetic acid. (7-Methoxy-2-methyl-3-quinolinyl)acetic acid can be treated with a reducing agent, such as, but not limited to, B2H6, borane-THF complex, or borane-pyridine complex, to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethanol. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethanol can be treated with methanesulfonyl chloride and a base, such as, but not limited to, triethylamine or diisopropylamine to provide 2-(7-methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate. 2-(7-Methoxy-2-methyl-3-quinolinyl)ethyl methanesulfonate can be treated with an amine of formula (5) to provide amines of formula (47). Amines of formula (47) can be treated with BBr3 to provide hydroxy compounds of formula (48). Hydroxy compounds of formula (48) can be treated with trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride to provide triflates of formula (49). Triflates of formula (49) can be treated with boronic acids of formula (7) as described in Scheme 1 to provide compounds of formula (50).
Reaction SMILES: C([NH:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]([C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=O)C.S(=O)(=O)(O)O.[CH3:23]O>>[NH2:4][C:5]1[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]([C:15]([O:17][CH3:23])=[O:16])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C(=O)O)c2c1OCCO2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)c2c1OCCO2
Reaction time: 20 h
Yield: 89 %

Procedure:
A stirred solution of 8-acetamido-1,4-benzodioxan-5-carboxylic acid (GB 1 571 278) (2.5 g, 0.0105 mole)in methanol (60 ml) was treated with concentrated sulphuric acid (2 ml) and the solution kept at room temperature for 20 hours, then concentrated in vacuo to approxiamately 10 ml volume. The residue was treated with water (30 ml), basified with potassium carbonate and a precipitate was produced. This was filtered off, washed with water and dried to afford methyl 8-amino-1,4-benzodioxan-5-carboxylate as a white solid (1.96 g, 89%). 1H NMR (CDCl3) δ:7.38(d,1 H), 6.28(d,1 H), 4.25-4.43(m,4 H), 4.12(br s,2 H), 3.83(s,3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCSCc1nccs1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1nccs1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)-thiomethyl]thiazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-thiazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-thiazolylmethylthio)ethyl]thiourea. Treating this compound with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH:15]=O.[C:17]1([CH2:23][C:24](OC)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[Na+].CN(C=O)C>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:6]2[N:5]=[CH:4][C:3]3[CH:15]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:24](=[O:25])[NH:1][C:2]=3[N:7]2[N:8]=1)([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)Cc1ccccc1
Reactant: CC(C)(C)c1cc2ncc(C=O)c(N)n2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2ncc3cc(-c4ccccc4)c(=O)[nH]c3n2n1
Temperature: 105 °C
Reaction time: 48 h
Yield: 45.7 %

Procedure:
A solution of 7-amino-2-tert-butylpyrazolo[1,5-a]pyrimidine-6-carbaldehyde (1.5 g, 6.87 mmol, 1.00 eq.), methyl 2-phenylacetate (4.1 g, 27.30 mmol, 4.00 eq.) and NaOtBu (1.3 g, 13.53 mmol, 2.00 eq.) in toluene (30 mL) was stirred at 105° C. for about 30 min under nitrogen. Then the reaction mixture was added 30 mL of DMF and the mixture was stirred for about 2 days at 105° C. After concentrating under vacuum, the residue was diluted with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6) to give the resulted product (1 g, 46%) as a yellow solid. LCMS (m/e)=319 (M+H); 1H NMR (300 MHz, DMSO, δ, ppm) 8.82 (s, 1H), 8.42 (s, 1H), 7.72 (d, J=6.9 Hz, 2H), 7.50-7.38 (m, 3H), 6.72 (s, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH:17]1(O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: OC1CCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.85 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.14 mmol cyclopentanol and 3.28 mmol triphenylphosphine in 10 ml THF was added 3.14 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 2:3) to afford the title compound as a colourless oil. MS (m/e): 312.1 ([M−H]−, 100%)
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.[ClH:28].CO>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Br:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Solvent: CO
Product: NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 1 (120 mg) prepared in Step A mentioned above is added with 10% hydrogen chloride/methanol (2 ml, Tokyo Kasei Kogyo), and the mixture is stirred at room temperature for 12 hours. The solvent is concentrated under reduced pressure, and the obtained solid is collected by filtration to obtain the title compound as hydrochloride (84 mg (predictive yield)).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>ClC(Cl)C>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnccc1O
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Yield: 76 %

Procedure:
5 g of 4-hydroxy-3-nitropyridine and 15.5 g of phosphorous pentachloride were added to 100 ml of dichloroethane and reacted under reflux for 90 minutes. When it was poured onto ice to separate an organic phase and allowed to stand at room temperature for a while, crystals were precipitated. They were collected by filtration and washed with hexane, to give 4.3 g of the title compound.