Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Reaction time: 4.5 h
Yield: 87.9 %

Procedure:
719 mg (1.37 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide under argon atmosphere, 932 mg (13.7 mmol) of imidazole and 657 mg (16.4 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred for 4.5 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:l) to give 600 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(imidazol-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].N>C1COCC1.CO.O>[F:1][C:2]1[C:3]2[NH:9][C:10](=[O:11])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(F)c1N
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cccc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES−) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.C(Cl)CCl.Cl.[CH3:39][NH:40][CH3:41]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([N:40]([CH3:41])[CH3:39])=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: CNC
Reactant: O=C(O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: CN(C)C(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (304 mg, 0.57 mmol), DMAP (138 mg, 1.13 mmol), EDC (217 mg, 1.13 mmol), and dimethylamine hydrochloride (93 mg, 1.13 mmol) in CH2Cl2 (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜30% EtOAc in hexane) to yield the title compound (122 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[C:19]([CH:14]1[NH:13][CH2:18][CH2:17][N:16]([C:8]2[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:7]=2)[NH2:6])[CH2:15]1)([OH:21])=[O:20]
Reactant: O=C(O)C1CNCCN1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OC1CCCCC1
Solvent: O
Product: Nc1cc(N2CCNC(C(=O)O)C2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 72.1 %

Procedure:
To a solution of 2.10 g of 4,5-dichloro-2-nitroaniline and 2.20 g of 2-piperazinecarboxylic acid in 20 ml of cyclohexanol, 4.80 g of sodium carbonate was added, followed by 14 hours' stirring at 150° C. After cooling the reaction liquid to room temperature, water was added and the system was washed with chloroform. The aqueous layer was purified with an ion-exchange resin (Diaion HP-20, Mitsubishi Kasei, eluent: methanol). Upon condensing the fraction containing the object product under reduced pressure, 2.20 g of the title compound was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[OH-].[Na+].[Cl-].[CH2:23]([N+:41]([CH3:44])([CH3:43])[CH3:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CC(C)=O>[CH2:23]([N+:41]([CH3:44])([CH3:42])[CH3:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].[C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH-:11])=[O:10])([OH:3])=[O:2]
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [NH-]C(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Reaction time: 0.25 h

Procedure:
Five g of the compound of Example 2 was slurried in 100 ml of 50% aqueous acetone, 0.67 g of sodium hydroxide was added, and the mixture was warmed and stirred for 15 minutes. Then 10.6 g of octadecyl-trimethylammonium chloride, 50% solution, was added and the mixture was stirred overnight. It was then extracted with 100 ml of ethyla acetate, and the organic layer was washed with brine and dried with sodium sulfate and phase separation paper. The extract was then evaporated under vacuum to obtain 9.95 g of the desired product, m.p. 141°-144°. It was identified by elemental and nuclear magnetic resonance analysis.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:15][OH:16])[CH:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[P:25](Cl)(Cl)([Cl:27])=[O:26].O>ClCCl>[Cl:27][P:25]1(=[O:26])[O:4][CH:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:17])([CH3:1])[CH2:15][O:16]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(CO)C(O)c1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(C)COP(=O)(Cl)OC1c1cccc2ccccc12
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
2,2-Dimethyl-1-(1-naphthyl)-1,3-propanediol (83.6 g, 0.363 mol) and triethylamine (103.0 g, 1.018 mol) were dissolved in dichloromethane (300 ml). Phosphorus oxychloride (55.4 g, 0.361 mol) dissolved in dichloromethane (80 ml) was added dropwise to the solution above under cooling (2 to 4° C.) and with stirring for 1.5 hr. The solution was stirred at the same temperature for 1 hr, and water (150 ml) was added thereto to partition. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained dark brown oil was added diethylether (100 ml) and diisopropylether (100 ml) and the mixture was stirred thoroughly and then ice-cooled for 1 hr. The upper layer containing a large amount of unreacted 1-naphthoaldehyde was removed by decantation and the under layer was concentrated to give the title compound as a black tar (76.1 g, yield 67.8%).
Reaction SMILES: C([O:3][P:4]([C:9]([P:30](=[O:37])([O:34]CC)[O:31]CC)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl.[2H]C([2H])(Cl)Cl.O1CCCC1.O>[C:17]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([P:30](=[O:31])([OH:34])[OH:37])[P:4](=[O:3])([OH:5])[OH:8])[CH:16]=[CH:15][CH:14]=1)#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC)c1
Agent: C[Si](C)(C)Br
Agent: [2H]C([2H])(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(O)O)P(=O)(O)O)c1
Reaction time: 6.5 h
Yield: 16 %

Procedure:
Tetraethyl[2-[3-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (3.247 g, 5.85 mmol) prepared according to Example 1 was dissolved in a mixture of CH2Cl2 -CD2Cl2 (25 ml, 4:1), and stirred under argon while trimethylsilyl bromide (3.5 ml, 26.5 mmol) was added. After the reaction was stirred for 6.5 hours, the solvent was removed under reduced pressure and the residue was briefly placed on the vacuum line. Hydrolysis was effected in tetrahydrofuran-water (9:1, 10 ml), stirring for 39 hours at room temperature. After stripping off the solvent, the residue was recrystallized from heptane-ether to give the product as a white solid, 0.416 g, 0.94 mmol, 16% yield; 1H NMR (CD3OD) ∂ 0.89 (t, J=6.9 Hz, 3H), 1.21 to 1.65 (several m, 18H), 2.40 (t, J=7.0 Hz, 2H), 7.55 (m, 2H), 7.71 (m, 2H), 8.03 (dd, J=46.1, 29.2 Hz, 1H); HRMS calcd for (M+H)+C21H33O6P2 m/z 443.1752, found 443.1700.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=[O:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH:11]([C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])=[CH:27][CH:28]=3)[N:7]2[CH:8]=1)=[O:12]
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Temperature: 80 °C

Procedure:
A mixture of compound 2a (100.0 mg, 0.320 mmol), 4-(tert-butoxycarbonyl)benzeneboronic acid pinacol ester (117 mg, 0.390 mmol), dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct (24.0 mg, 0.0320 mmol), and 1M sodium carbonate (1.61 mL, 1.61 mmol) in dioxane (6 mL) was purged with Argon gas. The resulting mixture was heated to 80° C. for 18 h. After the mixture was cooled, it was filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue was purified by Preparative TLC (EtOAc/CH2Cl2; 2:3, v/v) to give compound 81a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H25N4O4: 409.2 (M+H). found: 409.3.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5](=[O:15])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.CN1CCOCC1.[CH2:29]([S:36](Cl)(=[O:38])=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH2:8]([N:6]1[CH:7]=[C:2]([NH:1][S:36]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[C:3](=[O:21])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)Cn1c(=O)c(N)cn(Cc2ccccc2)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)Cn1c(=O)c(NS(=O)(=O)Cc2ccccc2)cn(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
EX-1C) A solution of 5-amino-1-Benzyl-3-methoxycarbonylmethyl-2,4(1H,3H) pyrimidinedione (EX-1B; 3.12 g, 10.77 mmol) in 18.0 mL of tetrahydrofuran and dimethylformamide (1:1, 0.62M) was added N-methyl morpholine (3.60 mL, 32.74 mmol) in one portion at room temperature. The resulting mixture was cooled to 0° C. in an ice bath and was allowed to stir for 15 minutes. A solution of benzylsulfonyl chloride (2.26 g, 11.86 mmol) in 18.0 mL tetrahydrofuran was added drop wise over a 30 minute period. After the addition was complete the reaction was stirred for 3 hours at 0° C. The reaction mixture was diluted with ethyl acetate (250.0 mL) and washed with 1N HCl ((2×50 mL), saturated NaHCO3 (2×50 mL), and brine (2×50 mL). The organic solution was dried (MgSO4), filtered and concentrated. Trituration with ethyl acetate and hexanes gave pure 1-Benzyl-3-methoxycarbonylmethyl-5-[[(phenylmethyl)sulfonyl]amino]-2,4(1H ,3H)pyrimidinedione (EX-1C) in 74% yield as a white solid: 1H NMR (300 MHz, DMSO) δ9.16 (s, 1H), 8.02 (s, 1H), 7.43-7.37 (m, 10H ), 5.01 (s, 2H), 4.65 (s, 2H), 4.45 (s, 2H), 3.69 (s, 3H);
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:3]=2[O:2]1.[NH:12]([CH2:19][CH2:20][C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(C)=O.C[O-].[Na+]>CO>[NH:12]([CH:19]=[C:20]([CH2:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)[C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCCNc1ccccc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: N#CC(=CNc1ccccc1)Cc1ccc2c(c1)OCO2
Temperature: 5 °C

Procedure:
Piperonaldehyde (45 g.), β-anilinopropionitrile (52 g.) and dimethylsulfoxide (96 ml.) were heated together to 120° C and a solution of sodium methylate (2.5 g.) in methanol (12 ml.) was added over a 5 min. period. The temperature was maintained at 115°-120° C for 1 hr. and the mixture was then poured into ice-water. The resulting gum was collected by decantation and was likewise washed with water (2 × 100 ml.). Methanol (100 ml.) was then added and the mixture was heated until solution was complete. Cooling to 5° C gave β-anilino-α-piperonylacrylonitrile as a crystalline solid which was collected, and washed with cold methanol, ether, and pentane. Wt=45 g. (54%) m.p. 150.5°-151° C (recrystallised from methanol).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[CH:28][CH:27]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:48]([O:52][C:53](=[O:56])[CH2:54]Br)([CH3:51])([CH3:50])[CH3:49]>C1COCC1.CN(C=O)C.C1COCC1>[C:48]([O:52][C:53](=[O:56])[CH2:54][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:47][CH:46]=1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCOCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To an ice-cooled suspension of sodium hydride (180 mg, 4.5 mmol; 60% in mineral oil) in THF/DMF (5/1 mixed solution 7 ml), a solution of Compound 24 (817 mg, 1.28 mmol) in THF (6 ml) was gradually added; this was followed by stirring for 30 minutes. A solution of bromoacetic acid tert-butyl ester (1.0 g, 5.1 mmol) in THF (7 ml) was added thereto. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, this was followed by extraction from ethyl acetate, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate solution containing 5% methanol)) to yield Compound 25 (light-yellow oil 655 mg, 68%).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][C@@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][C@@H:58]5[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 95.0 mg (0.146 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.4 ml of N,N-dimethylformamide, 92.4 mg (0.322 mmol) of (S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate and 54.2 mg (0.392 mmol) of potassium carbonate were added, and the mixture was stirred at 90° C. for 5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-59/41 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 91.3 mg of the title compound as a white solid (yield: 82%).
Reaction SMILES: O.NN.[C:4]([C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[CH:19][CH:20]=3)[C:15]([C:29](=O)[C:30]([OH:32])=[O:31])=[CH:14]2)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].C[O-].[Na+]>COCCO>[C:4]([C:8]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=4)=[CH:19][CH:20]=3)[C:15]([CH2:29][C:30]([OH:32])=[O:31])=[CH:14]2)=[CH:10][CH:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: Cc1cccc(-c2ccc3c(c2)c(C(=O)C(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1
Agent: C[O-]
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: Cc1cccc(-c2ccc3c(c2)c(CC(=O)O)cn3Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Hydrazine monohydrate (0.56 mL, 11.75 mmol) was added to a stirring solution of 2-[1-[4-(tert-Butyl)benzyl]-5-(3-methylphenyl)-1H-indol-3-yl]-2-oxoacetic acid (WAY-201417, 1.0 g, 2.35 mmol) in 2-methoxyethanol (10 mL). After the mixture was heated to 60° C. Sodium methoxide (1.34 g, 23.5 mmol) was added portionwise to the mixture. The reaction mixture was then slowly heated to 150° C., and concentrated. The mixture was kept stirring at 150° C. for 1 hour. The reaction mixture was cooled and poured onto ice water (100 mL). The aquoues mixture was extracted with methylene chloride and acidified with concentrated hydrocloric acid at 0° C. The organic extracts were washed with water and brine. Evaporation of the solvent and purification by flash column chromatography (5% methanol in methylene chloride) afforded an orange solid (0.452 g), m.p. 91-92° C. Mass spectrum [+ESI, (M+H)+] m/z 412. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 7.75 (s, 1H), 7.51 (d, 1H, J=8.55 Hz), 7.45 (s, 1H), 7.42-7.37 (m, 3H), 7.32-7.29 (m, 3H), 7.15 (d, 2H, J=8.25 Hz), 7.19 (d, 1H, J=7.48 Hz), 5.34 (s, 2H), 3.70 (s, 2H), 2.37 (s, 3H), and 1.22 ppm (s, 9H). Elemental Analysis for C28H27NO3 0.1 H2O Calculated: C, 81.36; H, 7.12; N, 3.39. Found: C, 81.15; H, 6.76; N, 3.52.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([OH:26])([CH2:23][CH2:24][CH3:25])[C:21]#[CH:22]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]#[C:21][C:20]([OH:26])([CH3:19])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(C)(O)CCC
Product: CCCC(C)(O)C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 with 3-methylhex-1-yn-3-ol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl)propyl)acetamide as dark brown oil. Yield (0.611 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.24-7.37 (m, 3H), 4.86 (m, 1H), 3.67-3.72 (m, 1H), 3.38-3.44 (m, 1H), 2.32 (bs, 1H), 1.94-2.01 (m, 3H), 1.71-1.76 (m, 2H), 1.59-1.62 (m, 1H), 1.53 (s, 3H), 0.99 (t, J=7.2, 3H).