Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[C@@H:15]([CH3:25])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.OO.[OH-].[Li+].[OH:31]S([O-])(=O)=O.[K+]>>[CH3:25][C@@H:15]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:14]([OH:26])=[O:31]
Reactant: O=S(=O)([O-])O
Reactant: C[C@@H](CCCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [K+]
Agent: [Li+]
Product: C[C@@H](CCCc1ccccc1)C(=O)O
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirring aqueous mixture cooled to 0° C. comprising (S)-4-benzyl-3-((S)-2-methyl-5-phenylpentanoyl)oxazolidin-2-one (21mb(i), 563 mg, 1.60 mmol) was added hydrogen peroxide and lithium hydroxide. The resulting reaction mixture was stirred for four hours. The reaction mixture was acidified with 5% KHSO4 and extracted twice with ethyl acetate, the organic layer was washed twice with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane-acetic acid (25:75:0.4) afforded the title compound (293 mg, 95%) as a colorless oil; TLC Rf 0.35 (solvent system: 25:75:0.4 v/v/v ethyl acetate-heptane-acetic acid); HPLC retention time 12.08 min, stationary phase: Chiralpak IA 4.6×25 mm 5μ, ultraviolet detector at 210 nm, mobile phase: 1 mL/min 99:1:0.1 heptane: 2-propanol:acetic acid, 97.22% (S), 2.78% (R).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]>O1CCCC1.CO.O>[CH3:4][O:5][C:6]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: COC(=O)c1ccc(C(C)(C)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Lithium hydroxide hydrate (0.40 g, 9.6 mmol) was added to a solution of methyl 4-(2-methoxypropan-2-yl)benzoate (0.10 g, 0.48 mmol) in tetrahydrofuran (9 mL), methanol (3 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was removed in vacuo. Hydrochloric acid (3 mol/L) was added to make pH 2-3, and the product was extracted with dichloromethane (50 mL). The combined organic phase was washed with sodium chloride aqueous solution (50 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give pure product 4-(2-methoxypropan-2-yl)benzoic acid (0.09 g, 96%) as a white solid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1.[CH:16]1([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][CH2:17]1.O>CN(C=O)C>[CH:16]1([CH2:19][N:20]([CH2:4][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH2:14][O:13][CH2:12][CH2:11][C:9]=3[N:10]=2)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:17][CH2:18]1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: CC(C)(C)OC(=O)NCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1nc2c(c(=O)[nH]1)COCC2)CC1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of NaH (11.96 g, 299 mmol) in 260 mL DMF at 0° C. was sequentially added 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (20 g, 100 mmol) and tert-butyl cyclopropylmethylcarbamate (17.07 g, 100 mmol) in small portions in order to maintain the internal temperature at or below 5° C. The reaction mixture was allowed to warm to room temperature slowly with continued stirring over 12 h. The reaction was cooled to 0 C and water was added slowly (˜250 mL total). The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated to a red oil. The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes and eluting with 100% ethyl acetate via a sharp gradient. The title compound was obtained as an off-white solid (20.79 g).
Reaction SMILES: C(OCl)(C)(C)C.FC(F)(F)[C:9]1[CH:10]=[C:11]([CH:13]=[C:14](C(F)(F)F)[CH:15]=1)[NH2:12].[CH3:22][S:23][CH2:24][C:25](OCC)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:22][S:23][C:24]1[C:25](=[O:26])[N:12]=[C:11]2[C:10]=1[CH:9]=[CH:15][CH:14]=[CH:13]2
Reactant: CCOC(=O)CSC
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1=c2ccccc2=NC1=O
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 103.5 %

Procedure:
Freshly prepared tBuOCl (2.2 g, 20 mmol) was added dropwise to a stirred cold (-65° C.) solution of 3,5-bis-(trifluoromethyl)aniline (4.58 g, 20 mmol) in anhydrous CH2Cl2 (25 mL). After 10 minutes, neat ethyl (methylthio)acetate (2.68 g, 20 mmol) was added and the mixture stirred at -65° C. for 1 hr. Triethylamine (2.68 g, 20 mmol) was added and then the mixture was allowed to warm to room temperature. The reaction mixture was quenched with water, the organic layer was separated and then rotary evaporated. The oily residue (6.35 g) was dissolved in hexanes and boiled for several hours and then allowed to cool. The precipitated beige solid was filtered and washed with hexanes to afford 3.67 g of pure (methylthio) indolone intermediate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH:21]=O)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([C@H:34]([C@@H:36]1[C@@H:40]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:39]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37]1)[OH:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[Si:42]([O:41][C@H:40]1[C@@H:39]([O:49][Si:50]([C:53]([CH3:55])([CH3:56])[CH3:54])([CH3:51])[CH3:52])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37][CH:36]1[C@H:34]([OH:35])[C@@H:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:25][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:11]([C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43]
Reactant: CC(C)C(O)C(NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@@H](O)C(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
A solution of [2-hydroxy-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (175 mg, 0.519 mmol, obtained from Reference Example 14) and tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (300 mg, 0.416 mmol, obtained from Reference Example 6) in anhydrous tetrahydrofuran was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (3 drops) and sodium triacetoxyborohydride (176 mg, 0.831 mmol) were added and the resulting solution was stirred under nitrogen for an additional 2.5 hours. The reaction mixture was basified to pH 9 with aqueous sodium carbonate solution, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (258 mg, 60%) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[C:6]([CH:12](O)[CH3:13])=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[C:6]([CH:12]([N:51]1[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]1=[O:52])[CH3:13])=[N:7]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol (0.08320 g, 0.2468 mmol) in tetrahydrofuran (2.468 mL, 0.2468 mmol) were added triphenylphosphine (0.07766 g, 0.2961 mmol), phthalimide (0.04357 g, 0.2961 mmol), and diisopropyl azodicarboxylate (0.05735 mL, 0.2961 mmol). The reaction mixture was stirred at room temperature. After 6 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 3 min as eluent to give 2-(1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl) ethyl)isoindoline-1,3-dione as a tan solid: LC-MS (ESD m/z 466.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(=O)CC(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCC(C(C)=O)C(=O)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate (3.84 g), and tetrabutylammonium bromide (90 mg) in toluene (20 ml) was refluxed for 3 hours, then ethyl 6-bromohexanoate (1.18 ml) was added. After stirring at 100° C. for 3 hours, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (983 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH:15]C(=O)OC(C)(C)C)[CH2:6]1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]([NH2:15])[CH2:6]1.[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31]
Reactant: CC(C)(C)OC(=O)NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccccc2N(Cc2ccc(F)cc2F)C1

Procedure:
tert-butyl 1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (365 mg) in trifluoroacetic acid and dichloromethane (1:4, v/v) was stirred at room temperature for 3 hours. After removing all the volatiles, toluene (5 mL) was added to the residue and evaporated again. The residue was then dried over vacuum overnight to give 1-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-amine as its TFA salt.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:19][CH2:18][C:17]2[C:8](=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[O:7]1)=O)C.[BH4-].[Li+].CO>O1CCCC1.C(OCC)(=O)C>[NH:13]1[C:14]2[C:9](=[C:8]3[C:17](=[CH:16][CH:15]=2)[CH2:18][CH2:19][CH:6]([CH2:4][OH:3])[O:7]3)[CH2:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1CCc2ccc3c(c2O1)CCCN3
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: OCC1CCc2ccc3c(c2O1)CCCN3
Temperature: 25 °C
Reaction time: 48 h
Yield: 122.1 %

Procedure:
To 1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester (0.80 g, 3.1 mmole) in 25 mL of tetrahydrofuran was added 0.22 g (10 mmole) of lithium borohydride. The mixture was stirred for 48 hours at room temperature. Methanol (5 mL) was added and stirring at room temperature continued for an additional hour. The mixture was then diluted to 300 mL with ethyl acetate and washed with 100 mL portions of water and saturated brine and dried over sodium sulfate. Filtration and concentration in vacuum gave 0.83 g of the title compound as a white solid. 1H-NMR (CDCl3): doublet 6.65 δ (1H); doublet 6.1 δ (1H); multiplet 4.1 δ (1H); multiplet 3.8 δ (2H); multiplet 3.2 δ (2H); broad singlet 2.8 δ (1H); multiplet 2.55 δ (4H); multiplet 1.9 δ (2H); multiplet 1.2 δ (2H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3](OCC)=[O:4].[K].C(C(C(Cl)=O)C(Cl)=O)C.[NH3:22]>>[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([NH2:22])=[O:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: [K]
Product: CCOC(=O)CC(N)=O

Procedure:
Biguanide was prepared fresh by refluxing anhydrous biguanide sulfate in a methanol solution of freshly prepared sodium methylate by the method of Slotta et al. (Slotta, K. H., Tschesche, R., Ber. Dtsch. Chem. Ges. 1929, B62, 1390-1398). The biguanide was used in solution as prepared for all of the reactions. Because sodium sulfate formed in the preparation of biguanide did not interfere with subsequent reactions, it was not necessary to separate it from the biguanide. Ethyl malonamate used in the preparation of Ib (see Example 1 below) was prepared as follows by methods of Galat and Marguery (Galat, A., J. Am. Chem. Soc. 1948, 70, 2596 and Marguery, M. F., Bull. Soc. Chem. France 1905, 33, 541; J. Recherces Centr. Natl. Recherche Sci., Labs. Bellevue (Paris) 1959, 47, 147), through Chem. Abstr. 1962, 56, 4744 g.): Diethyl malonate was converted to the mono-potassium salt of the half-ester. The latter was converted to ethyl malonyl chloride, which in turn was reacted with anhydrous ammonia in ice-cold ether to form ethyl malonamate.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH3:29])=[CH:13][CH:12]=2)[CH:5]=1.O[Li].O>C1COCC1.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:30])=[O:2])=[CH:12][CH:13]=2)=[C:20]([CH3:29])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: COC(=O)c1cccc(Cc2ccc(CNc3ccc(C(C)=O)c(O)c3C)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(NCc2ccc(Cc3cccc(C(=O)O)c3)cc2)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To 3-{4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-benzyl}-benzoic acid methyl ester (356 mg, 0.88 mmol) in THF (14 mL) is added a solution of LiOH.H2O (185 mg, 4.4 mmol) in H2O (7 mL). The reaction mixture is stirred at RT overnight. The reaction mixture is acidified to pH=7 and concentrated. The residue is purified by reverse phase HPLC using 90:10 to 20:80 (H2O/0.1% TFA)/CH3CN. Obtained is the title compound as a brownish solid (158 mg, 46%). LC-MS (m/e): 390 (M+1); 1H NMR (DMSO-d6) δ 13.16 (1H, s), 12.84 (1H, bs), 7.71 (2H, m), 7.43 (2H, m), 7.36 (1H, dd), 7.19 (2H, d), 7.14 (2H, d), 6.75 (1H, t), 6.05 (1H, d), 4.38 (2H, d), 3.92 (2H, s), 2.35 (3H, s), 1.94 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][CH2:11][CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:5][CH:4]=1.N1CCCCC1.O.C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][CH2:11][CH:12]2[NH:13][CH2:14][CH:15]([OH:17])[CH2:16]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(OCC2CC(O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: O
Product: COc1ccc(C(OCC2CC(O)CN2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(9H-Fluoren-9-yl)methyl 2-((bis(4-methoxyphenyl)(phenyl)-methoxy)methyl)-4-hydroxypyrrol-idine-1-carboxylate (3.4 g, 5.3 mmoles) is dissolved in anhydrous N,N-dimethylformamide (15 mL). The solution is stirred at ambient temperature, and piperidine (1.1 mL, 11. mmoles) is added. After 1 hour, a copious white precipitate has formed. Water (100 mL) and ethyl acetate (75 mL) are added, and the mixture is stirred until all of the solid has dissolved. The layers are separated and the aqueous layer is extracted with ethyl acetate (75 mL). The combined ethyl acetate layers are washed with saturated aqueous sodium bicarbonate (50 mL) then saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated to an amorphous white solid. The crude product is purified on silica gel (150 mL bed volume) eluting with methylene chloride:methanol:triethylamine (94:1:5 [v/v/v], 700 mL; then 90:5:5 [v/v/v], 700 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a white glassy foam, which is dried well in vacuo. The yield is 2.2 g (99%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:38])=[C:27]([C:29]3[C:30]([C:36]#[N:37])=[CH:31][CH:32]=[C:33]([F:35])[CH:34]=3)[CH:28]=2)OC1>>[F:35][C:33]1[CH:34]=[C:29]([C:27]2[CH:28]=[C:23]([C:2]3[C:3]4[C:8](=[N:7][C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:24]=[CH:25][C:26]=2[F:38])[C:30]([C:36]#[N:37])=[CH:31][CH:32]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cc(F)ccc3C#N)c2)OC1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: N#Cc1ccc(F)cc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 29.8 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5,2′-difluorobiphenyl-2-carbonitrile (91 mg, 0.28 mmol) as described in Example 7 part g), affording 5,2′-difluoro-5′-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)biphenyl-2-carbonitrile (27 mg, 30%). δH (360 MHz, CDCl3) 7.24-7.29 (1H, m), 7.34 (1H, dt, J 7.2 and 1.9), 7.46-7.51 (1H, m), 7.59-7.65 (3H, m), 7.84-7.90 (2H, m), 8.68 (1H, d, J 8.8), 9.29 (1H, d, J 4.2). m/z (ES+) 412 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[C:12]([O:17]CC4C=CC=CC=4)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26]>C(O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=3[CH:10]=[C:9]2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26]
Reactant: Cc1cc2c(OCc3ccccc3)cccc2n1-c1ccc(O)c(F)c1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2c(O)cccc2n1-c1ccc(O)c(F)c1
Yield: 50.2 %

Procedure:
To a solution of 2-fluoro-4-{2-methyl-4-[(phenylmethyl)oxy]-1H-indol-1-yl}phenol (D3) (85 mg, 0.24 mmol) in ethanol (7 mL) was added a solution of tetra-n-butylammonium chloride (170 mg, 0.61 mmol) in ethyl acetate (1 mL). The solution was hydrogenated in an H-cube over a 10% Pd/C catalyst. The resulting solution was concentrated and the product purified by MDAP to yield the title compound (E3) (31 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]([N+:14]([O-:16])=[O:15])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.[CH:25]1([CH2:31]I)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:31][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:13])[C:5]=2[N+:14]([O-:16])=[O:15])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: ICC1CCCCC1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Product: COC(=O)Cn1c(C)cc(CC2CCCCC2)c([N+](=O)[O-])c1=O
Yield: 50.4 %

Procedure:
This compound is prepared from 3 g (8 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)-sulphonyl]oxy]-1,2-dihydropyridine-1-acetate and 5.45 g (24.3 mmol) of cyclohexylmethyl iodide according to the method described in Example 1.5. 1.3 g of product are obtained in the form of yellow crystals.
Reaction SMILES: [C:1]([CH:3]=[C:4](OC)[O:5][CH3:6])#[N:2].[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[C:1]([CH:3]=[C:4]([O:5][CH3:6])[NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:2]
Reactant: NCCSCc1ncccc1Cl
Reactant: COC(=CC#N)OC
Product: COC(=CC#N)NCCSCc1ncccc1Cl

Procedure:
Reaction of 1-cyano-2,2-bis-methoxyethylene (J.A.C.S., 1949, 71, 47) with 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine by the procedure of Example 1(b)(i) yields 1-cyano-2-methoxy-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]ethylene
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)#[N:15]
Reactant: Nc1cnc2ccccc2c1
Reactant: C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Reaction time: 20 h
Yield: 51.6 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide (97 mg, 0.430 mmol), 3-aminoquinoline (62 mg, 0.430 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)propanamide (74 mg).