Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[CH2:19]([C@H:21]1[CH2:26][NH:25][C@H:24]([CH3:27])[CH2:23][N:22]1[CH2:28][C:29]([OH:31])=[O:30])[CH3:20]>C(Cl)Cl>[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[C:4]([O:3][C:1]([N:25]1[CH2:26][C@H:21]([CH2:19][CH3:20])[N:22]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][C@H:24]1[CH3:27])=[O:8])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC[C@H]1CN[C@H](C)CN1CC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.1 %

Procedure:
tert-Butyl dicarbonate (2.1 g, 9.6 mmol) and triethylamine (6.7 mL, 48.4 mmol) were added to a suspension of ((2S,5R)-2-ethyl-5-methyl-piperazin-1-yl)-acetic acid (1.8 g, 9.6 mmol) in DCM. The resulting solution was stirred at room temperature for 24 h. The solvent was removed in vacuo to give (2R,5S)-4-carboxymethyl-5-ethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester triethylamine salt (3.8 g) as a yellow gum. 1H NMR (CDCl3): 11.73-9.75 (1H, m), 4.20 (1H, s), 3.86 (1H, d), 3.34-3.07 (3H, m), 2.97 (6H, q, triethylamine), 2.77-2.65 (2H, m), 2.60 (1H, dd), 1.47-1.36 (11H, m), 1.26 (3H, d), 1.24-1.14 (9H, m, triethylamine), 0.87 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7](OC)=[O:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][OH:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(C)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(CO)cc1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution (4 mL) of the compound (0.80 g) obtained in Example 128c in tetrahydrofuran was cooled in an ice bath, and lithium aluminum hydride (0.16 g) was added by small portions. The reaction mixture was stirred at the same temperature for 1 hr, water (0.16 mL), 15% sodium hydroxide (0.16 ml) and water (0.48 mL) were successively added, and the mixture was stirred at room temperature for 15 min. The insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.64 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.[Mg].[CH:16](Br)=C>O1CCCC1>[CH3:16][CH:5]1[C:6]([CH3:14])([CH3:13])[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11])[C:2]([CH3:1])=[CH:3][CH2:4]1
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Reactant: C=CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)/C=C/C1C(C)=CCC(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 50 g (0.26 mol) of α-ionone in 150 ml of tetrahydrofuran was allowed to drop over a period of 20 minutes into a Grignard solution, which was cooled to 0° C. and which had been prepared from 9.72 g (0.4 mol) of magnesium shavings in 75 ml of tetrahydrofuran and 44.9 g (0.42 mol) of vinyl bromide in 180 ml of tetrahydrofuran, in such a manner that the temperature lay between 15° C. and 20° C. Subsequently, the mixture was stirred at room temperature for a further 3 hours and worked-up as described in Example 8. There were obtained 54.5 g of crude product which contained above 92% 9-vinyl-α-ionol according to GC and which was further processed directly in this form. In a manner analogous to the epoxidation of α-irone (Example 4), from 53.2 g (0.242 mol) of 9-vinyl-α-ionol there was obtained 59.0 g of crude 9-vinyl-α-ionol epoxide of which 58.0 g were dissolved together with 26.5 g (0.13 mol) of aluminium isopropylate in 175 ml of isopropanol. By following the procedure described in Example 1 there were obtained 57 g of a crude product. From this crude product there were obtained by distillation over a 20 cm Widmer column 15.0 g (26%) of olfactorily good product of boiling point 73°-74° C./0.3 mmHg which contained above 85% 20a and 20b in the approximate ratio of 3:2. In addition, there were present small amounts of the corresponding 7-oxa-bicyclooctane 20c. ##STR33##
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:25]N(C=O)C>ClC(Cl)C>[C:1]1([S:7][C:8]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:25])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1

Procedure:
A solution of 2-(phenylsulphenyl)-4-trifluoromethylbenzoic acid (11.5 g) and thionyl chloride (11.4 g) in dichloroethane containing a few drops of DMF was heated at reflux for 1.5 hours. The mixture was evaporated to dryness and methanol was added. The mixture was heated at reflux for 1 hour and evaporated to dryness. It was treated with water and extracted with ether, washed with sodium carbonate solution (2M), water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with cyclohexane and filtered to give methyl 2-(phenylsulphenyl)-4-trifluoromethylbenzoate (10.5 g) as a white solid, m.p. 55°-60° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[OH:29][CH:30]([CH3:51])[CH2:31][N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[C:33]1=[O:50]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[C:39]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:50])[N:32]([CH2:31][CH:30]([OH:29])[CH3:51])[CH2:40]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC(O)CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CC(C)O)C5=O)c3cn2)c1F

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(2-hydroxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=481.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][N:20]([CH2:22][C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:59])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)[CH3:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:60][CH3:61])=[C:10]([CH2:19][N:20]([CH2:22][C:23]3[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=3)[C:29]([NH:31][CH2:32][C:33]3[CH:38]=[C:37]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]5[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]5)[CH:40]=4)[C:36]([F:59])=[CH:35][CH:34]=3)=[O:30])[CH3:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)Cc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)Cc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-({[(3-{[{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(methyl)amino]methyl}phenyl) carbonyl]amino}methyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.055 g, 0.066 mmol) in DCM (0.25 mL) was added TFA (0.25 mL) and stirred at room temperature for 30 min before was diluted with DCM, basified with NaHCO3 (sat. aq.). Organic layer was separated, dried over Na2SO4, filtered, concentrated, purified using a Gilson HPLC (with TFA), final product was basified with an amine cartridge to afford 0.015 g (31%) of the title compound. LC-MS m/z 733 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.24 (t, J=7.40 Hz, 3 H) 1.48 (t, J=7.15 Hz, 3 H) 1.70-1.85 (m, J=10.79 Hz, 2 H) 2.01-2.11 (m, J=12.55, 1.76 Hz, 2 H) 2.56 (s, 3 H) 2.83-2.97 (m, J=7.28 Hz, 2 H) 3.46-3.58 (m, J=5.77 Hz, 8 H) 3.59-3.68 (m, 2 H) 3.92-4.00 (m, J=12.05 Hz, 2 H) 4.01-4.26 (m, J=29.11 Hz, 4 H) 4.26-4.35 (m, 1 H) 4.41-4.50 (m, 4 H) 4.61 (s, 2 H) 7.19 (dd, J=10.67, 8.41 Hz, 1 H) 7.39-7.45 (m, 1 H) 7.50-7.60 (m, 4 H) 7.61-7.70 (m, 2 H) 7.74 (s, 1 H) 7.86 (d, J=8.03 Hz, 1 H) 7.95 (s, 1 H) 8.25 (s, 1 H).
Reaction SMILES: [O:1]1CCCO[CH:2]1[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[C:19]([F:28])[CH:18]=2)[CH2:11][CH2:10]1.C(O)C.C(O)=O>[Pd].C1(C)C=CC=CC=1>[F:28][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH:12]2[CH2:13][CH2:14][CH:9]([CH2:8][CH2:7][CH:2]=[O:1])[CH2:10][CH2:11]2)[CH:22]=[CH:21][C:20]=1[O:23][C:24]([F:26])([F:27])[F:25]
Reactant: Fc1cc(C=CC2CCC(CCC3OCCCO3)CC2)ccc1OC(F)(F)F
Agent: [Pd]
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=CCCC1CCC(CCc2ccc(OC(F)(F)F)c(F)c2)CC1
Yield: 37.2 %

Procedure:
The above 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene (5.5 g, 13.7 mmol) was hydrogenated in the presence of 5% Pd/C catalyst (0.3 g) in an ethanol solution, followed by filtering off the catalyst, distilling off the solvent under reduced pressure, adding formic acid (2.8 g, 60.8 mmol) and toluene (50 ml) to the residue, refluxing the mixture for 5 hours, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over MgSO4, and distilling off the solvent, to obtain 3-(4-(2-(3-fluoro-4-trifluoromethoxyphenyl)ethyl)cyclohexyl)propanal (1.76 g, 5.1 mmol). The yield of this product from 1-(2-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)vinyl-3-fluoro-4-trifluoromethoxybenzene was 37.2%.
Reaction SMILES: [O:1]1CCCC1.B.[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]([CH:37]=[CH2:38])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]=1[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41].C([O-])(=O)C.[Na+].OO.Cl>C1COCC1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]([CH2:37][CH2:38][OH:1])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]=1[CH2:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: C=CC(CC(=O)OCC)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Reactant: C1CCOC1
Agent: B
Agent: CC(=O)[O-]
Agent: Cl
Product: CCOC(=O)CC(CCO)c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, a solution (1.1 M, 5.2 mL) of tetrahydrofuran-borane in THF was added to a solution of ethyl 3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)oxy)methyl)phenyl)pent-4-enoate (1.44 g) in THF (25 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added aqueous sodium acetate solution (3.0 M, 25 mL) and aqueous hydrogen peroxide (30%, 4.4 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (440 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[I:12].[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:13])[N:6]=[C:5]2[I:12]
Reactant: CC(C)(C)[O-]
Reactant: Clc1cc2[nH]nc(I)c2cc1Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(Cl)c(Cl)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of 5,6-dichloro-3-iodo-1H-indazole (820 mg, 2.62 mmol) in THF (8 ml) at 0° C. was added KOt-Bu (412 mg, 3.67 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.23 ml, 3.67 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 1.5 hr. The reaction was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was absorbed on silica gel and purified by chromatography with 20% to 30% EtOAc/hexanes to afford 585 mg (68%) of 5,6-dichloro-3-iodo-1-methyl-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.61 (s, 1H), 7.56 (s, 1H), 4.09 (s, 3H). The minor 5,6-dichloro-3-iodo-2-methyl-1H-indazole regioisomer was also observed but not isolated.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)(Cl)=O.ClC(NC(=O)C1C=CC=NC=1)C(Cl)(Cl)Cl.[CH:35]([SH:39])([CH2:37][CH3:38])[CH3:36].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C1C=CC=CC=1>[CH:35]([S:39][CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4])([CH2:37][CH3:38])[CH3:36]
Reactant: CCC(C)S
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cccnc1
Agent: O=C(NC(Cl)C(Cl)(Cl)Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCC(C)SC(NC(=O)c1cccnc1)C(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 39.4 %

Procedure:
150 ml of benzene was added to 5.0 g of N-(1-hydroxy-2,2,2-trichloroethyl)nicotinamide. 2.6 g of thionyl chloride was added dropwise to the mixture under stirring. Then, the mixture was heated under reflux (60° to 80° C.) for about 5 h to complete the production of N-(1,2,2,2-tetrachloroethyl)nicotinamide. The reaction liquid was cooled to 30° C. or below and 1.7 g of sec-butylmercaptan was added thereto. 3.7 g of triethylamine was added dropwise to the liquid mixture while it was kept at 5° C. The obtained mixture was stirred at room temperature for 3 h and then left to stand at room temperature overnight. The reaction liquid was poured in an aqueous sodium bicarbonate solution and a benzene layer thus separated was washed with a saturated aqueous common salt solution and water and then dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 2.5 g of N-(1-sec-butylthio-2,2,2-trichloroethyl)nicotinamide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24].[C:25]([O:29][C:30]([NH:32][C@H:33]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH3:49])[CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[O:35]=[C:34]([NH:1][CH:2]1[CH2:11][C:10]2[C:5](=[C:6]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:3]1=[O:24])[C@H:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH3:49])[CH:39]=1
Reactant: CCCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CCCn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC2Cc3cccc(N4CCCC4=O)c3N(Cc3ccsc3)C2=O)c2ccccc21
Yield: 107 %

Procedure:
The procedure of Example 14(a) was repeated, except that (−)-3-amino-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-3,4-dihydroquinolin-2(1H)-one (500 mg) and (R)-2-(tert-butoxycarbonylamino)-3-(1-propyl-1H-indol-3-yl)propanoic acid (641 mg) synthesized in Referential Example 1(d) were used, whereby the title compound (1.05 g) was yielded.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=1>CO.[C].[Pd]>[NH2:19][C:18]1[CH:17]=[CH:16][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.8 %

Procedure:
To a solution of methyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate (200 mg) in methanol (40 ml) was added 10% palladium carbon, followed by stirring under a hydrogen atmosphere at room temperature for 4.5 hrs. The reaction mixture was filtered to remove the catalyst, which was then washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (181 mg) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([CH3:28])[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:25]2[CH:26]=[C:21]([Cl:20])[N:22]=[C:23]([CH3:28])[N:24]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](O)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(C)n2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of 1(R)-1-[4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (15.7 g, 46.3 mmol, Intermediate 1) in dioxane (200 mL) was added 4,6-dichloro-2-methylpyrimidine (30.6 g, 51 mmol) and Cs2CO3 (61.2 g, 187 mmol). The reaction mixture was heated to 80° C. for 30 h, then cooled to RT, and filtered. The residue was concentrated in vacuo and purified by normal phase column chromatography on silica gel (CH2Cl2/heptane) to provide (R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].O1CCCCC1[N:36]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[N:37]1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:38]3[NH:37][N:36]=[CH:40][CH:39]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 10 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 14.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a pale yellow powder. UPLC-MS (Condition 3) tR=0.96 min, m/z=466.2 [M+H]+, m/z=464.2 [M−H]−. 1H-NMR (400 MHz, DMSO-d6) d ppm 2.77 (s, 3H) 3.38-3.61 (m, 4H) 4.61 (br. s, 1H) 6.47 (s, 1H) 7.68 (d, J=8.56 Hz, 2H) 7.83 (br. s, 1H) 7.93 (d, J=8.80 Hz, 2H) 8.15 (br. s, 1H) 8.71 (br. s, 1H) 10.36 (s, 1H) 12.83-13.15 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][N:14]3[C:17]3[N:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[NH2:23][C:19]1[N:20]=[CH:21][N:22]=[C:17]([N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][C:25]([Cl:24])=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=5)[CH:7]=[CH:6][CH:5]=4)[CH:16]=3)[CH:12]=[CH:13]2)[CH:18]=1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cccc(-c2ccc3ccn(-c4cc(N)ncn4)c3c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc(-n2ccc3ccc(-c4cccc(NC(=O)c5ccc(Cl)c(C(F)(F)F)c5)c4)cc32)ncn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-(6-(3-Aminophenyl)-1H-indol-1-yl)pyrimidin-4-amine (15 mg, 0.050 mmol), 4-chloro-3-(trifluoromethyl)benzoic acid (16.8 mg, 0.075 mmol) and HOBt (6.8 mg, 0.050 mmol) were dissolved in THF (1 mL). At room temperature, EDCI (28.8 mg, 0.15 mmol) was added. The reaction solution was stirred at room temperature for 15 hours and the reaction mixture was added to saturated sodium bicarbonate aqueous solution. After adding water and ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx=1:4→MC:MeOH=20:1) yielded the target compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(#N)C>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:19]=[C:20]([S:24]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1OC

Procedure:
As described under 1.2., 4.1 g (0.02 mol) of a-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 5.4 g (0.022 mol) of 3-trifluoromethylphenylsulfonic acid chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/-hexane, 6.6 g (80%) of α-(3-trifluoromethyl-phenylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 129-130° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 351 nm (ε=11700) that extends to 430 nm. Elemental analysis: C17H13F3N2O5S (414.36)