Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1B(O)O>>[CH:30]1[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:29]=1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc4ccccc4c3)nc2c1
Yield: 46.7 %

Procedure:
The ester product was obtained via a Suzuki coupling reaction using the method previously shown in Example 13, Step 6, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.34 mmol, 1.00 equiv) and naphthalen-2-yl boronic acid (63 mg, 0.37 mmol, 1.10 equiv). Purification via silica gel column (ethyl acetate/petroleum ether (1:20)) yielded 62 mg (47%) of methyl 3-(naphthalen-2-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([NH:43]O)=[NH:42])=[CH:39][CH:38]=2)[CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]2=[O:35])(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:41]3[N:42]=[C:1]([CH3:2])[O:4][N:43]=3)=[CH:45][CH:46]=2)[CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:29]2=[O:35])(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: CC(=O)O
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a solution of acetic acid (63 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.43 g (91%) 4-chloro-N-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=474.9 (MH+, 100).
Reaction SMILES: [N:1]1([C:7]2[C:12]([Br:13])=[CH:11][N:10]=[C:9]([CH2:14][S:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:18]=4[N:17]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:27]1CCN(C2C3N(Cl)CN(SCC4C=CC=CN=4)C=3C=CC=2OC)CC1>>[N:1]1([C:7]2[C:12]([Br:13])=[CH:11][N:10]=[C:9]([CH2:14][S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:18]=4[N:17]=3)=[O:27])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2[nH]c(SCc3cc(N4CCCCC4)c(Br)cn3)nc2c1
Reactant: COc1ccc2c(c1N1CCOCC1)N(Cl)CN2SCc1ccccn1
Product: COc1ccc2[nH]c(S(=O)Cc3cc(N4CCCCC4)c(Br)cn3)nc2c1

Procedure:
Substituting 2-(4-piperidino-5-bromo-2-pyridylmethylthio)-5-methoxy-(1H)-benzimidazole (3.83 g) for 2-(4-morpholino-3-chloro-2-pyridylmethylthio-5-methoxy-(1H)-benzimidazole and using corresponding molar proportions of the other reagents in the method of Example 4 gave after chromatography (silica gel, chloroform:methanol-ammonia) 2-(4-piperidino-5-bromo-2-pyridylmethylsulphinyl)-5-methoxy-(1H)-benzimidazole, 3.15 g, m.p. 114°-8° C., from ether.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(Nc2ccc(Cl)cc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(Cl)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-chloro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-chloroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: C1([C@H](OC(=O)[NH:11][C@@H:12]2[C@@H:21]([O:22][CH3:23])[CH2:20][C:19]3[C:14](=[CH:15][C:16]([OH:24])=[CH:17][CH:18]=3)[C:13]2([CH2:27][CH3:28])[CH2:25][CH3:26])C)C=CC=CC=1.Cl.O1CCOCC1>>[NH2:11][C@H:12]1[C:13]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:14]2[CH:15]=[C:16]([OH:24])[CH:17]=[CH:18][C:19]=2[CH2:20][C@@H:21]1[O:22][CH3:23]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.8 %

Procedure:
((2S,3S)-1,1-Diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (635 mg, 1.60 mmol) was treated with 4.0 N HCl in dioxane (6.0 mL, 24 mmol) and stirred at RT. After 3 days, the solvent was removed at reduced pressure and the residual solid was triturated with 50% dichloromethane in heptane (4 mL). The solid was collected on a Buchner funnel and dried under vacuum to give the title compound (462 mg). (m/z): [M+H]+ calcd for C15H23NO2 250.36; found 250.2. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 9.23 (s, 1H), 8.02 (br s, 3H), 6.92 (d, J=8.2 Hz, 1H), 6.61 (m, 2H), 3.77 (m, 1H), 3.41 (s, 3H), 3.30 (m, 1H), 3.17 (m, 1H), 2.44 (dd, J=15.9 Hz, 9.8 Hz, 1H), 1.85 (m, 2H), 1.62-1.52 (m, 2H), 0.66 (t, J=7.2 Hz, 3H), 0.55 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>COC(C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A mixture of pyridine-3-sulfonic acid (10.3 g, 64.8 mmol), phosphorus pentachloride (20.82 g, 100 mmol) and phosphorus oxychloride (10 mL, 109 mmol) was heated to reflux for 3 h (according to J. Org. Chem. 1989, 54(2), 389). Evaporated to dryness to give a yellow solid, dissolved in ice water and methyl-tert-butyl ether, added cautiously sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum to give the title compound as an orange liquid (10.85 g, 94%). MS (ISP) 178.1 [(M+H)+] and 180.0 [(M+2+H)+].
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH:8]=[C:7]1[O:17]C)(=[O:3])[CH3:2].I[Si](C)(C)C>C(#N)C>[C:1]([O:4][CH2:5][C:6]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][C:7]1=[O:17])(=[O:3])[CH3:2]
Reactant: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(C)=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(=O)OCC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of Example 179C (0.12 g, 0.38 mmol) in acetonitrile (3.5 mL) was added iodotrimethylsilane (TMSI) (81 μL, 0.57 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (81 μL) were added and stirring was continued for 2 h. The solution was quenched with water (3 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (70% ethyl acetate/hexane) afforded product as a white solid (91%). 1H NMR (300 MHz, CDCl3) δ ppm 0.55 (s, 1 H), 0.77 (m, 12 H), 0.93 (m, 2 H), 1.36 (m, 3 H), 1.79 (m, 8 H), 2.19 (m, 3 H), 3.77 (m, 2 H), 4.42 (d, J=11.03 Hz, 1 H), 4.57 (m, 3 H), 6.15 (s, 1 H), 7.46 (m, 4 H), 7.59 (m, 1 H), 7.69 (m, 1 H), 8.12 (m, 2 H); MS m/z 303.0.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](O)(=[O:11])[CH3:10]>>[C:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Valine (1 g, 8.53 mmol) and acetic acid (20 mL) were mixed together and heated at 150° C. in a microwave for one hour. The excess acetic acid was removed using a rotary evaporator. The residue was stirred in MTBE at ambient temperature for one hour. The mixture was filtered and the solid was washed with MTBE. The solid was dried in a vacuum oven at 60° C. The product was obtained as a white solid (1.13 grams, 83.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.74-0.98 (m, 6H), 1.81-1.96 (m, 3H), 1.97-2.18 (m, 1H), 4.13 (dd, 1H), 7.99 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[CH2:3][CH2:2][O:1][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH3:31])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: Cc1ccc(N=C=O)cc1
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:35]([NH:38][C:39](=[O:42])[CH2:40]Br)([CH3:37])[CH3:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:35]([NH:38][C:39](=[O:42])[CH2:40][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(O)c4)nc4ccccc34)ccc21
Reactant: CC(C)NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A solution of tert-butyl 5-(2-(3-hydroxyphenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.3 g, 0.66 mmol), N-isopropylbromoacetamide (0.132 g, 0.726 mmole), and K2CO3 (0.183 g, 1.32 mmole) in DMF (3.6 mL) was heated overnight at 30° C. The crude product was poured onto ice-water (ca. 50 mL) and the suspension was stirred for approximately 0.5 h, filtered and dried (Na2SO4). The crude product was recrystallized from absolute EtOH (10 mL) to afford tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.160 g, mmol, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.N1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=[C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[C:30]([CH3:37])[CH:29]=3)[CH2:24]2)[CH:19]=[C:20]([Cl:22])[CH:21]=1>ClCCl>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:25]3[CH2:24][C:23]([C:18]4[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=4)([C:38]([F:41])([F:40])[F:39])[O:27][N:26]=3)=[CH:29][C:30]=2[CH3:37])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)n1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Cl)n1
Yield: 68.8 %

Procedure:
In a solution of 0.10 g of 2-amino-6-chloropyridine and 0.16 g of pyridine in 5 mL of dichloromethane, a solution of 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 5 mL of dichloromethane was added at room temperature with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, and precipitated insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.25 g of the aimed product as colorless resinous substance.
Reaction SMILES: O1CCCC[C@@H]1O[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.O.C1(C)C=CC(S(O)(=O)=[O:31])=CC=1>CO>[OH:31][C@@H:9]([CH3:8])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1ccc(OCCCO[C@H]2CCCCO2)cc1
Solvent: CO
Solvent: O
Product: CCOC(=O)c1ccc(OC[C@H](C)O)cc1
Yield: 891.8 %

Procedure:
A mixture of 4.5 g (0.014 mol) of (S)-ethyl 4-(2-tetrahydropyranyloxy)propoxybenzoate, 0.2 g (0.0011 mol) of p-toluenesulfonic acid monohydrate and 45 ml of methanol were refluxed for 1 h. Then the same procedure as in Referential Example 2 was repeated to obtain 2.2 g of the crude product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:9][C:10]([C:12]#[C:13][C:14](OCC)=[O:15])=[O:11])[CH3:8]>C(O)C>[CH2:7]([O:9][C:10]([C:12]1[N:6]2[CH:5]=[CH:4][S:3][C:2]2=[N:1][C:14](=[O:15])[CH:13]=1)=[O:11])[CH3:8]
Reactant: Nc1nccs1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sccn12
Reaction time: 8 h

Procedure:
5 g of 2-aminothiazole are dissolved in 50 ml of ethanol and 8.5 g of acetylene dicarboxylic acid diethyl ester are added to the resulting solution. The mixture increases in temperature and a solid substance begins to precipitate. After standing overnight, it is filtered off, washed with a little ethanol and dried. 7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 173° to 175° C. is thus obtained in a yield of 8.2 g (85.4% of the theoretical).
Reaction SMILES: C([Mg:3][Br:4])C.Br[C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16]>C(OC)(C)(C)C>[F:12][C:11]1[C:6]([Mg:3][Br:4])=[C:7]([F:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[F:13]
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Reactant: CC[Mg]Br
Solvent: COC(C)(C)C
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Air inside a reaction vessel of the same type as the one used in Example 1 was replaced with a nitrogen gas in a satisfactory manner, after which 130 ml of a t-butyl methyl ether (chain ether solvent) solution containing 0.198 mol of suspended ethyl magnesium bromide as the hydrocarbon magnesium halide (2) was charged to the reaction vessel. Meanwhile, 0.182 mol of bromopentafluorobenzene was charged to the dropping funnel. Then, bromopentafluorobenzene in the dropping funnel was dropped to the reaction vessel over 45 minutes at room temperature, and the reaction solution was stirred for 4 hours at room temperature. Consequently, pentafluorophenyl magnesium bromide was obtained in the form of a colorless t-butylmethyl ether solution. The yield of pentafluorophenyl magnesium bromide measured in the same manner as Example 1 was 98.0 mol % based on bromopentafluorobenzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].[C:7](N=[N+]=[N-])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>O.O1CCOCC1>[C:7]([NH:1][CH2:2][CH2:3][OH:4])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a cooled, stirred solution of 2-aminoethanol (5.9 ml, 0.098 mol) and sodium hydroxide (3.6 g, 0.098 mol) in water-dioxane (1:1), was added drop-wise Boc-azide (10 ml, 0.081 mol). The reaction was stirred at room temperature overnight. The dioxane was then removed under vacuum, and the water layer extracted several times with ethyl acetate. The organic layer was dried over sodium sulphate and then, evaporated to dryness under vacuum to get the product (N-Boc)-2-aminoethanol (5.37 g, 41% yield), which was used in further steps without purification.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:21])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:21][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(N)c1-c1nnnn1Cc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Reaction time: 8 h
Yield: 63.8 %

Procedure:
2-(1-Benzyl-1H-tetrazol-5-yl)-3-methoxyphenylamine (Intermediate 13, 0.115 g) was dissolved in pyridine (0.16 mL) and DCM (2 mL). Benzenesulfonyl chloride (0.08 g) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a colorless solid (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])=O.Cl.[NH2:22][OH:23]>N1C=CC=CC=1.C(OC(=O)C)C>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:22]\[OH:23])/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14]
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)c(O)c1Cl
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(/C(=N\O)c2cccc(F)c2F)c(O)c1Cl

Procedure:
To a solution of 24 g of 3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone in 160 ml pyridine, 22 g of hydroxylamine HCl is added. The mixture is refluxed for 2 hours and the pyridine evaporated in vacuo. The residue is partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a pale yellow solid which consists of two isomers. The solid is melted at 205° C. for approximately 13 minutes. The residue is dissolved in hot ethylacetate and then evaporated to dryness giving E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 198°-199° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:32]2[CH:33]=[CH:34][C:29]([CH3:28])=[CH:30][CH:31]=2)[C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-n2c(C(=O)N3CCOCC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-methylbenzeneboronic acid. The title compound was obtained in 57% yield as a yellow foam. MS (m/e): 462.2 (MH+, 100%).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>O1CCOCC1>[CH:1]([C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1cccc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=Cc1cccc2ccoc12
Yield: 23 %

Procedure:
0.950 g (6.4 mmol) of 7-formyl-2,3-dihydrobenzofuran, 1.82 g (8 mmol) of 2,3-dichloro-5,6-dicyanocyclohexa-2,5-diene-1,4-dione (DDQ) and 30 ml of dioxane are introduced into a 100 ml three-necked flask equipped with a reflux condenser. Heating is carried out at reflux for 24 hours. 100 ml of a molar sodium hydroxide solution are added and extraction is carried out with ethyl ether (3×80 ml). The organic phases are combined, dried and concentrated under vacuum. The residue is purified by silica flash chromatography (elution: 5% ethyl acetate in petroleum ether). 215 mg of 7-formylbenzofuran are obtained in the form of a yellow oil (Yield: 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[C:20](Cl)(=[O:22])[CH3:21].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:20](=[O:22])[CH3:21])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2ccc(-c3cc(F)ccc3C)cc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (2 mL) was added acetyl chloride (56 mg, 0.714 mmol) dropwise at a temperature below 0° C. After the resulting mixture was stirred at room temperature for 2 h, water (2 mL) was added and it was concentrated under reduced pressure. The solid was washed with methanol and water to give the desired product (26.7 mg, 15.2%). LCMS (ESI): RT (min)=1.150, M+H+=294.8, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.62, (s, 1H), 9.14 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 2.22 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)Cl
Reactant: OCCCCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCCCO
Temperature: 0 °C

Procedure:
z,z,z-Octadeca-6,9,12-trienoyl chloride (2 g) was added dropwise to a solution of 1,5-dihydroxypentane (3.5 g), triethylamine (0.94 ml) and 4-(N,N-dimethylamino)pyridine (0.2 g) in methylene chloride (50 ml) with stirring at 0° C. under nitrogen. On completion of reaction as evidenced by tic the reaction mixture was washed with dilute hydrochloric acid and water, dried and purified by column chromatography yielding 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane as a pale yellow oil.