Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.O.[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.Cl>CO.C(O)(C)C>[OH:7][C:8]1[C:16]([CH:8]([CH3:16])[CH3:9])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH:11]([CH3:12])[CH3:10]
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O
Temperature: 62.5 °C

Procedure:
360 ml sulphuric acid was added slowly to 25 ml chilled water at 10-15° C. to a round bottom flask supplied with a mechanical stirrer. To this stirred mass was charged p-hydroxy benzoic acid 100 g (0.72M) lot wise followed by Isopropyl alcohol 130 g (2.16M) at a temperature below 15° C. The reaction mass was finally heated to 60-65° C. for 4 hrs. After reaction completion the reaction mass was quenched in caustic solution and washed two times with toluene (400 ml). The aqueous layer obtained was acidified using aq. HCl solution. Precipitated solid was washed twice, each time with 250 ml of hot water and dried to obtain crude product. Crude solid was dissolved in 350 ml of methanol and treated with activated carbon, filtered and added into 1000 ml chilled water at about 10-15° C. The precipitate was filtered off and washed twice with 200 ml of water each time. After drying under vacuum at 70-75° C. up to a constant weight, 4-hydroxy-3,5-diisopropyl benzoic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=O)=[CH:17][CH:16]=1>>[OH:12][C:4]1[CH:3]=[C:2]2[C:10]([N:11]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=3)=[N:1]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1cc(O)c(C(=O)O)cc1N
Product: COc1ccc(-c2nc3cc(O)c(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 12.4 %

Procedure:
The diaryl product was obtained using the same synthetic methods as shown in Example 25, step 7, using 4,5-diamino-2-hydroxybenzoic acid (168 mg, 1.00 mmol, 1.00 equiv) and 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (270 mg, 1.00 mmol, 1.00 equiv) as reactants, yielding 50 mg (12%) of 7-hydroxy-2,3-bis(4-methoxyphenyl)quinoxaline-6-carboxylic acid as a red solid.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.C[O-].[Na+].[Cl:16][C:17]1[C:28]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:27][C:20]([NH:21][C:22](=O)[O:23]CC)=[C:19]([F:35])[CH:18]=1>CN(C)C=O>[Cl:16][C:17]1[C:28]([NH:29][S:30]([CH2:33][CH3:34])(=[O:32])=[O:31])=[CH:27][C:20]([N:21]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:22]2=[O:23])=[C:19]([F:35])[CH:18]=1
Reactant: CCOC(=O)Nc1cc(NS(=O)(=O)CC)c(Cl)cc1F
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 5 °C
Yield: 77 %

Procedure:
1.06 g (5.77 mmol) of ethyl 3-amino-4,4,4-trifluorocrotonate was dissolved in 6.2 ml of N,N-dimethylformamide and 0.82 g (14.4 mmol) of sodium methoxide was added thereto. The reaction mixture was cooled to not higher than 5° C. after 10 minutes, and 1.56 g (4.81 mmol) of ethyl 4-chloro-5-ethylsulfonylamino-2-fluorocarbanilate was added thereto. The resultant mixture was heated to 110° C. and reacted for 4 hours. After the reaction was completed, N,N-dimethylformamide was distilled off and the resultant product was dissolved in water. The thus-obtained solution was washed with diethyl ether 3 times and thereafter concentrated hydrochloric acid was added thereto to pH 2. The precipitated crystals were filtered out, washed with water and dried to obtain 1.54 g of the objective product (yield: 77%) in the form of light yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:21][C:22](O)=[O:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:40]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N.Cl>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([O:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:21][C:22]([NH2:40])=[O:23])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)CCCCCCCCCCCC(CC(=O)O)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CCCCCCCCCCCC(CC(N)=O)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(N-tertiarybutoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoic acid (2.30 g) in tetrahydrofuran (30 ml) was added 1-hydroxybenzotriazole (0.58 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.82 g). The mixture was stirred at room temperature for 30 minutes. 28% Ammonia solution (0.5 ml) was added to the mixture and then the mixture was stirred at room temperature for 2 hours. The mixture was poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with chloroform to give 3-(N-tertiarybutoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanamide as white wax (1.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[C:31]([F:45])[CH:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33](=[O:34])[NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[C:31]([F:45])[CH:30]=1
Reactant: NCc1ccc(C(=O)NC2CCCCCC2)c(F)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCCC1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F
Yield: 53.3 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.5 mmol) with 4-aminomethyl-N-cycloheptyl-2-fluoro-benzamide (1.35 g, 5.1 mmol) in anhydrous toluene (25 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient) followed by SCX chromatography to obtain 7-chloro-6-[4-cycloheptylcarbamoyl-3-fluoro-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (720 mg, 53%). MS (ES+) m/z: 540.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[NH:21][C:20](=[O:22])[N:19]([CH:23]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)=[O:25])[C:18]=2[CH:51]=1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:21]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:20](=[O:22])[N:19]([CH:23]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)=[O:25])[C:18]=2[CH:51]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)C(c3ccccc3)n3c(=O)[nH]c4ccc(Cl)cc43)CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)CC3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
167 mg (0.81 mmol) of 4-methoxybenzenesulfonyl chloride were added to a solution of 460 mg (0.73 mmol) of tert-butyl 4-{-4-[2-(6-chloro-2-oxo-2,3-dihydrobenzimidazol-1-yl)-2-phenylacetyl]-piperazin-1-yl}piperidin-1-carboxylate (XIIIa), 0.21 ml (1.47 mmol) of triethylamine and a catalytic amount of DMAP in tetrahydrofuran (8 ml) while stirring at room temperature, and the mixture was then stirred at room temperature for 16 h. The reaction solution was mixed with water and extracted with ethyl acetate (3×60 ml). The combined organic phases were washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase gradient 5-10% methanol in dichloromethane). Yield: 517 g (97%) of colorless oil
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH2:30](B(O)O)[CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:30][CH2:31][CH2:32][CH3:33])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: CCCCB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)OC)c(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), n-butylboronic acid (340 mg), tetrakis(triphenylphosphine)palladium(0) (80 mg), potassium carbonate (280 mg), toluene (6 ml) and THF (3 ml) was stirred at 100° C. under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and crystallized from hexane to give the title compound (210 mg).
Reaction SMILES: [C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:30](=[O:37])([O:34]CC)[O:31]CC)[P:22](=[O:29])([O:26]CC)[O:23]CC)[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[Si](Br)(C)C>C(Cl)Cl.O1CCCC1.O>[C:1]([C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([P:30](=[O:31])([OH:34])[OH:37])[P:22](=[O:23])([OH:26])[OH:29])[CH:17]=[CH:18][CH:19]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1cccc(C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: C1CCOC1
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: [C:1]1([CH2:7][C:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[C:39](Cl)(=[O:50])[O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1>C(Cl)Cl>[N+:47]([C:44]1[CH:43]=[CH:42][C:41]([O:40][C:39](=[O:50])[NH:10][CH2:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=2)[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:46][CH:45]=1)([O-:49])=[O:48]
Reactant: NCC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(NCC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a solution of 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propan-1-amine (1.37 g, 3.00 mmol), prepared as described in Example 10 (Procedure 13, 14, 15, and 16), in CH2Cl2 (35 mL) was added K2CO3 (2.1 g, 15 mmol) followed by 4-nitrophenyl carbonochloridate (806 mg, 4.0 mmol) and the reaction mixture was stirred at rt for 5 h. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with 1N Na2CO3 (6×50 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 0 to 40% EtOAc/hexane to yield [3-phenyl-2,2-bis-(3-trifluoromethoxy-phenyl)-propyl]-carbamic acid 4-nitro-phenyl ester (1.50 g, 81% yield) as a clear, colorless oil. LCMS: RT=2.30 min [M+H] 620.94 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) ppm 3.42 (s, 2 H), 3.92 (d, J=6.15 Hz, 2 H), 4.72 (t, J=5.71 Hz, 1 H), 6.60 (d, J=7.03 Hz, 2 H), 7.05-7.26 (m, 9 H), 7.37 (t, J=8.13 Hz, 2 H), 8.23 (d, J=9.23 Hz, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][NH:36][CH3:35])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-formylphenyl)benzamide (150 mg), methylamine (38% in methanol, 0.5 ml) and 3 Å molecular sieves (500 mg) in methanol (10 ml) was stirred at ambient temperature overnight. Sodium borohydride (39 mg) was added to the solution and the mixture was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-methylaminomethylphenyl)benzamide (160 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][O:27][C:28]2=[O:33]>ClCCl>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:23][C:24]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:25]=2[CH2:26][O:27][C:28]3=[O:33])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(OCC)c1ccc(C=Nc2cccc3c2COC3=O)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 84.5 %

Procedure:
To a stirred mixture of 4-(diethoxymethyl)benzaldehyde (3.75 g, 18 mmol) and anhydrous sodium sulfate (21.3 g, 150 mmol) in anhydrous dichloromethane (300 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.24 g, 15 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give 4-(4-(diethoxymethyl)benzylideneamino)isobenzofuran-1(3H)-one (4.3 g, yield 84%) as a light yellow solid. LC-MS (ESI) m/z: 340 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([OH:13])([C:9]([F:12])([F:11])[F:10])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:42]12([C:52](Cl)=[O:53])[CH2:51][CH:46]3[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]3)[CH2:43]1)[CH2:49]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:42]12([C:52]([O:13][C:3]([C:2]([F:1])([F:14])[F:15])([C:9]([F:12])([F:10])[F:11])[CH2:4][S:5]([O-:8])(=[O:7])=[O:6])=[O:53])[CH2:49][CH:48]3[CH2:47][CH:46]([CH2:45][CH:44]([CH2:50]3)[CH2:43]1)[CH2:51]2.[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)([O-])CC(O)(C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Into a mixture solution of 5.2 g (10 mmoles) of triphenylsulfonium 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropane-1-sulfonate prepared in Synthesis Example 1-9, 1.1 g (11 mmoles) of triethylamine, 0.24 g (2 mmoles) of 4-dimethylaminopyridine, and 21 g of methylene chloride was added 5.5 g (11 mmoles) of a methylene chloride solution of adamantane-1-carbonyl chloride (40% by weight), and they were stirred at room temperature for 2 hours. Thereafter, the reaction was terminated by adding 12 g of 5% hydrochloric acid, and then the organic layer was separated, washed by water, and concentrated under reduced pressure. Into the concentrated solution was added methyl isobutyl ketone, and the resulted mixture was concentrated again under reduced pressure to distil the remaining water out. The obtained residue was washed by diisopropyl ether, and then dried to obtain the intended triphenylsulfonium 2-(adamantane-1-carbonyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (2.7 g of oily substance (yield 39%)). The structure of the intended product is shown below.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27].Cl[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(N(CC)CC)C>CS(C)=O.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:6][C:5](=[O:25])[N:4]([CH3:26])[C:3]1=[O:27]
Reactant: Cn1c(NCCNCCCNc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Reactant: COC(=O)CCl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CN(CCCNc1ccc([N+](=O)[O-])cc1)CCNc1cc(=O)n(C)c(=O)n1C
Yield: 100.7 %

Procedure:
1.5 g of 1,3-dimethyl-6-{2-[3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound b) obtained in the above procedure (3) were dissolved in 12 ml of DMSO, followed by the addition of 1.2 g of methyl chloroacetate and 1.5 ml of triethylamine. The resultant mixture was stirred at 50° C. for 2 hours, dissolved in chloroform, washed with water and then dried over anhydrous sodium sulfate. The solvent was thereafter distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=30/1, by volume), thereby obtaining 1.8 g of 1,3-dimethyl-6-{2-[N-methoxycarbonylmethyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(-c2cccc(Cl)c2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
To 120 mg (0.1 mmol) of above resin-bound bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide in 2.0 mL of DME were added 48.0 mg (0.3 mmol) of 3-chlorophenylboronic acid, 30 mg (0.03 mmol) of Pd(PPh3)4, and 0.3 mL (0.6 mmol) of 2N Na2CO3 solution. The mixture was heated to 80° C. for 12 h. The resin was washed with H2O, DMF, MeOH, DCM three times of each and cleaved with TMSBr/TFA/DCM (1:1:5) at rt for 4 h. The residue obtained after removing the solvent was purified by chromatography (silica gel, DCM) to give 20 mg (40%) of the title compound.