Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[OH2:24]>CO>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[C:2](=[O:1])[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[C:5](=[O:24])[C:4]=1[CH3:12]
Reactant: O
Reactant: COc1cc(C)c(CCCCCCCCCCO)c(O)c1OC
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reaction time: 2 h
Yield: 96.9 %

Procedure:
In methanol (5.4 l) was dissolved 10-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)decan-1-ol (271 g), to which was added an aqueous solution of disodium nitrosodisulfonate (6.7 l, content 0.359 mol./l) synthesized by means of electrolytic oxidation. The mixture was stirred for two hours while keeping the temperatures at 50°±2° C. After confirmation of disappearance of the starting material by thin-layer chromatography, water (8.6 l) was added to the reaction mixture, followed by extraction twice with toluene (5.5 and 2.7 l). The toluene layers were combined and washed with water. The toluene layer was concentrated under reduced pressure to obtain a crude product, 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (288 g, content 94.8%, yield 96.9%). This crude product (20 g) was recrystallized from a mixture of toluene (60 ml) and n-hexane (180 ml). The crystals were dissolved in toluene (60 ml), and the solution was allowed to pass through a precoated layer of activated alumina (30 g). The filtrate was concentrated under reduced pressure, and the concentrate was recrystallized again from a mixture of toluene (55 ml) and n-hexane (165 ml). The crystals were further recrystallized from 50% ethanol (108 ml), followed by drying to obtain 6-(10-hydroxydecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (16.2 g) as orange-yellow crystals, m.p. 54.0° C.
Reaction SMILES: [C:1]1([N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN1CCC(N(c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCC(N(c2ccccc2)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A solution of ethyl 2-(4-(phenyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)-acetate (1.1 g, 3 mmol) and sodium hydroxide 1N (4 ml, 4 mmol) in MeOH (15 mL) was heated to 70° C. with stirring for 2 h. Upon cooling to RT, the solvent was removed under reduced pressure. The residue was dissolved in water and the pH adjusted to 4 with 2 N HCl. The solution was extracted with DCM. The DCM layers were combined, dried (Na2SO4), and concentrated. The residue was purified with ISCO using 0-15% MeOH in DCM to give 2-(4-(phenyl(3-(trifluoromethyl)phenyl)amino)piperidin-1-yl)acetic acid (0.8 g, 78% yield). MS (ESI, pos. ion) m/z: 379.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=1)[NH:32][CH:31]=[CH:30]2.C([SiH](CC)CC)C>ClCCl>[Br:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:11]1[CH2:10][CH2:9][S:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12]1
Reactant: O=C1CCSC(c2ccccc2)C1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CCSC(c4ccccc4)C3)c[nH]c12
Reaction time: 2 h

Procedure:
To a solution of 2-phenylthian-4-one (SJTU) (0.900 g, 4.68 mmol) in dichloromethane (DCM) (15 mL), cooled on an ice bath to 0° C., under argon, was added dropwise trimethylsilyl trifluoromethanesulfonate (1.807 mL, 10 mmol) over 10 minutes, an additional portion of dry DCM (5 mL) was used to wash the addition funnel walls. To this mixture ethyl 5-bromo-1H-indole-7-carboxylate (1.340 g, 5.00 mmol) was added dropwise, in solution with of dry DCM, over 2 hours. Finally, triethylsilane (3.19 mL, 20 mmol) was added in one portion and the mixture was stirred 2 h at ca 0° C., and left stirring at 23° C. 16 h. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate, and the resulting biphasic mixture partitioned with DCM to afford 2.21 g of brow gummy oil. LCMS of product may indicate an overlapping mixture of ca 5:2 major to minor isomers (cis/trans).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:33]2[N:32]=[CH:31][C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([O:14][C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2ccc(OC(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M187) (242 mg, 0.436 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (93 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:34][CH3:35].[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:34][CH3:35]
Reactant: COC(=O)c1ccc(C2CC(c3cc(C(=O)NCc4ccc(F)c(OC)c4)nc(C)n3)=NO2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(=O)O)cc4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold stirred solution of methyl 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoate (0.3 g, 0.62 mmol, G.1.29) in THF/water (1:1) was added lithium hydroxide (0.03 g, 1.2 mmol, Sd Fine Chem). The reaction mixture was stirred for about 3 h at RT and excess solvent was removed under reduced pressure. The aqueous layer was acidified with 10% HCl solution. The solid was collected by filtration, washed with water and dried under vacuum to afford 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid. (0.2 g), (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:34]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:34][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(F)c1)CC2
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 475.22 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 3-fluoro-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.BrC1C(NCC(OC)=O)=NC=C(Br)N=1.C[O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)CN.C(N(C(C)C)CC)(C)C>CS(C)=O>[OH:37][C:38]1[CH:39]=[CH:40][C:43]([C:2]2[N:7]=[C:6]3[N:8]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=4)[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:44][CH:45]=1
Reactant: COc1cccc(CN)c1
Reactant: COc1cccc(CN2C(=O)CNc3ncc(Br)nc32)c1
Agent: COC(=O)CNc1ncc(Br)nc1Br
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN2C(=O)CNc3ncc(-c4ccc(O)cc4)nc32)c1
Yield: 20 %

Procedure:
7-Bromo-1-(3-methoxybenzyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Methyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (0.58 g, 1.8 mmol), 3-methoxybenzylamine (227 μL, 1.8 mmol), diisopropylethylamine (1 mL), and dimethylsulfoxide (1 mL) were heated to 100° C. for 3 d under nitrogen. The reaction was extracted with ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column (0-100% ethyl acetate in hexanes) to give the title compound (124 mg, 20% yield) as a pink solid. MS (ESI) m/z 349.0 [M+1]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(=[O:7])=[O:6]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(=[O:7])=[O:6]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)n1ccc2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A solution of [1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indol-5-yl]-methanol (2.1 g, 6.74 mmol) in methylene chloride (30 mL) was added at 0° C. to a mixture of activated manganese dioxide (22 g, azeotropically dried with toluene (2×)) and methylene chloride (70 mL) in a 500 mL round bottom flask. The reaction mixture was stirred at 0° C. for 30 min and filtered through a pad of celite. Solvents were removed in vacuo to afford the title compound as a white solid (1.8 g, 80%). 1H-NMR (CDCl3, 500 MHz) δ 10.06 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.87 (dd, J=8.6, 1.5 Hz, 1H), 7.54 (d, J=3.4 Hz, 1H), 6.80 (d, J=3.6 Hz, 1H), 3.24–3.20 (m, 2H), 0.86–0.82 (m, 2H), −0.06 (s, 9H). 13C-NMR (CDCl3, 125 MHz) δ 191.9, 138.5, 132.3, 130.7, 128.8, 125.3, 125.1, 1134.6, 108.4, 51.4, 10.2, −2.1. Mass spec. 310.12 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH:33]([F:35])[F:34])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:17]([NH2:25])=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:26]3[CH2:31]C[NH:29][CH2:28][CH2:27]3)[N:9]=2)[CH:7]=1.C(OC(N[C@H]1C[C@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:29][CH:28]1[CH2:31][CH:26]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[C:17]([NH2:25])=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:32][CH:33]([F:35])[F:34])=[N:9]2)[CH2:27]1
Reactant: Nc1nn2cccnc2c1C(=O)Nc1cn(C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F
Agent: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)cc1
Product: Nc1nn2cccnc2c1C(=O)Nc1cn(C2CC(N)C2)nc1-c1cc(Cl)ccc1OC(F)F

Procedure:
The title compound was prepared in an analogous manner to 2-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxy-phenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]-amide using tert-butyl (3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl) carbamate and trans-toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-cyclobutyl ester to afford the title compound as a white solid. LCMS (Method 5) [M+H]+=489.1, RT=2.87 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.53 (s, 1H), 8.93 (dd, 1H, J=1.6, 6.8 Hz), 8.37-8.34 (m, 2H), 7.63-7.60 (m, 2H), 7.45 (d, 1H, J=7.2 Hz), 7.25 (t, 1H, J=72.6 Hz), 7.00 (dd, 1H, J=4.5, 6.5 Hz), 6.56 (s, 2H), 4.51-4.41 (m, 1H), 3.18-3.07 (m, 1H), 2.75-2.67 (m, 2H), 2.24-2.14 (m, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([C:19]([NH2:21])=O)=[CH:17][C:16]([C:22]([F:25])([F:24])[F:23])=[N:15]2)=[CH:11][CH:10]=1.C(OCC)(=O)C.CCCCCC.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][NH2:21])=[CH:17][C:16]([C:22]([F:23])([F:24])[F:25])=[N:15]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(Cn2nc(C(F)(F)F)cc2C(N)=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C(F)(F)F)cc2CN)cc1

Procedure:
LAH (4.7 g, 0.12 mol) was charged into a flask. THF (250 mL) was added at 0° C. Then a solution of 1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (37 g, 0.12 mol) in THF (120 mL) was added drop wise for 30 min at 0° C. and reaction mixture was heated to reflux for 5 h. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.2). As the reaction was not completed, LAH (2.3 g) was added again and the mixture was refluxed for another 4 h. After completion of the reaction, the reaction contents were slowly added to saturated sodium sulfate (1 L) solution and filtered over celite and the product was extracted with ethyl acetate (2×500 mL). The combined extract was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude (1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine as an off white solid (32.5 g, crude). The crude product obtained was directly used for the next step.
Reaction SMILES: [Na].[C:2]([NH:10][C@H:11]([C:22]([OH:24])=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:2]([NH:10][C:11](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1)[C:22]([OH:24])=[O:23])(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(C[C@H](NC(=O)c2ccccc2)C(=O)O)ccc1O
Agent: [Na]
Product: COc1cc(C=C(NC(=O)c2ccccc2)C(=O)O)ccc1O

Procedure:
Assay of the resulting solution shows an optical purity of 56.4% corresponding to a 78/22 L/D mixture of the sodium salt of N-benzoyl-3-(4-hydroxy-3-methoxyphenyl)-alanine.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.Br[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][OH:56]>>[Cl:46][C:41]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][OH:56])=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:12][CH:13]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Reactant: OCCc1ccccc1Br
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCO)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and commercially available 2-(2-bromophenyl)ethanol as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].S([O-])([O-])(=O)=S.[Na+].[Na+].[Na+].[Cl-]>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N+:33]=3[O-:9])=[CH:28][CH:27]=2)=[O:38])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccn3)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cccc[n+]3[O-])cc2)CC1
Reaction time: 24 h

Procedure:
At −10° C., metachloroperbenzoic acid (789 mg) was added to a solution of 1-tert-butoxycarbonyl-4-[4-(2-pyridyl)benzoyl]piperazine (517 mg) in dichloromethane (dichloromethane: 8 ml). The resulting mixture was stirred for 24 hours, followed by dilution with dichloromethane. A small amount of an aqueous sodium thiosulfate solution and a saturated aqueous NaCl solution were added to the dilute solution. The organic layer so separated was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol=20:1), whereby the title compound (415 mg, 77%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:23]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:17]([N:23]1[C:31]2[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCCCCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCCCCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
108 mg of compound 7 was obtained in a similar manner to those described in the Examples 1 and 2 using 580 mg of ethyl 4-(2-aminophenoxy)butyrate and 366 mg of 3-(1-hexylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH:9]=[C:8]1[C:16]([O:18]CC)=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[CH:31]=1>>[CH3:30][C:28]1[S:29][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:16]([C:8]3[N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[CH:9]=3)=[O:18])=[CH:31][C:26]=2[N:27]=1
Reactant: CCOC(=O)c1cc2cccnc2n1-c1ccccn1
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(NC(=O)c3cc4cccnc4n3-c3ccccn3)ccc2s1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.2, starting with ethyl 1-(2-pyridyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 8.1 and 5-amino-2-methylbenzothiazole. A white solid is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cccc(C)c2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a nitrogen stream, to a solution of 2-benzyloxy-3-methyl-benzaldehyde (1.87 g, 8.25 mmol) in THF (50 mL), a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 19.8 mL) was added dropwise under cooling with ice. The mixture was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (2.76 g, 100%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([C:32]1[CH:33]=[C:34]([NH:43][CH2:44][C:45]([OH:47])=O)[C:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.CCN(CC)CC>CN(C=O)C>[CH2:25]([C:32]1[CH:33]=[C:34]([NH:43][CH2:44][C:45]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])[C:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
HATU (494 mg, 1.3 mmol) was added via spatula to a solution of N-[5-benzyl-2-(ethoxycarbonyl)pyridin-3-yl]glycine (328 mg, 1.04 mmol), morpholine (0.113 mL, 1.3 mmol) and Et3N (0.18 mL, 1.3 mmol) in DMF (6 mL). After stirring for 45 min at rt, the solvent was removed in vacuo and the resulting material was dissolved in CH2Cl2 and washed with water. The organic layer was dried and concentrated. Purification of the crude material by silica gel chromatography eluting with 0-5% MeOH/CH2Cl2 afforded the product: 1H NMR (CDCl3) δ 8.57 (1H, br), 7.94 (1H, s), 7.23 (3H, m), 7.15 (2H, m), 6.68 (1H, s), 4.46 (2H, q, J=7 Hz), 3.95 (2H, s), 3.90 (2H, d, J=4.2 Hz), 3.68 (6H, br), 3.43 (2H, br), 1.42 (3H, t, J=7 Hz); ES+ MS: 384 (M+H+, 70).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH2:7]([C@H:2]([NH:1][C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])[C:3]([OH:5])([CH3:4])[CH3:6])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(O)[C@@H](N)Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(O)[C@H](Cc1ccccc1)NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a solution of (8) (2.573 g, 14.37 mmol) in pyridine (50 ml) at 0° C. was added trichloroacetyl chloride (1.93 ml, 17.25 mmol). After stirring at this temperature for 10 minutes, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (9) (4.093 g, 88%) as a solid; mp 88° C.; νmax (CDCl3) 1713 cm-1 ; [α]D24 (c 0.8 in CHCl3)=-26.8; (Found: C, 48.32; H, 4.61; N, 4.13. C13H16Cl3NO2 requires C, 48.16; H, 4.97; N, 4.32%); δH (300 MHz; CDCl3) 1.32 (3H, S, C(CH3)2), 1.40 (3H, s, C(CH3)2), 1.91 (1H, s, OH), 2.75 (1H, dd, J=10.9 and 14.2, CH2Ph), 3.20 (1H, dd, J=4.04 and 14.2, CH2Ph), 4.04-4.13 (1H, m, CHCH2), 6.80 (1H, d, J=9.3, NH); δC (125 MHz; CDCl3) 27.18 (CH3), 27.74 (CH3), 35.43 (CH2), 60.25 (CH), 72.92 (C), 93.00 (CC13), 126.89 (CH), 128.78 (CH), 129.33 (CH), 137.66 (C), 162.07 (CO); m/z (CI+, NH3) 324 (M+).