Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([N:20](S(CC2C=CC=CC=2)(=O)=O)[S:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([C:8]1[C:9]([NH:20][S:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccccc1)N(c1ncc(-c2ccccc2)nc1Cc1ccccc1)S(=O)(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(Cc1ccccc1)Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
3-Benzyl-2-bis(benzylsulfonyl)amino-5-phenylpyrazine (c-42) (1.15 g, 2.02 mmol) was suspended in methanol (24 mL), and to this was added 10% (w/v) aqueous solution of sodium hydroxide (5.7 mL) while stirring at room temperature and then stirred at 65° C. for 30 min. After cooling to room temperature, to this was added 2 M hydrochloric acid to stop the reaction and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was recrystallized from ethyl acetate to give 3-benzyl-2-benzylsulfonylamino-5-phenylpyrazine (dideoxycoelenterasulfonamide) (c-37) as a colorless solid (662 mg, 78.9%). Rf=0.62 (n-hexane/ethyl acetate=3/2). Mp. 207-208.5° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 322.5 (4.01), 285.5 (4.08), 261 (4.14). UV (pH 7.4 PB, 0.3% DMSO) λmax (log ε) 343 (4.01), 280.5 (4.07). 1H NMR (400 MHz, DMSO-d6) δ 4.26 (s, 2H), 4.94 (s, 2H), 7.15-7.21 (m, 1H), 7.23-7.30 (m, 4H), 7.36 (s, 5H), 7.40-7.53 (m, 3H), 8.04 (d, J=7.0 Hz, 2H), 8.95 (s, 1H), 10.55 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6/CD3OD=2/1) δ 38.5, 60.1, 126.7 (2C), 126.8, 128.8 (2C), 128.9, 129.0 (2C), 129.4 (2C), 129.5 (2C), 129.7, 130.4, 131.4 (2C), 136.3, 137.3, 138.5, 145.8, 146.3, 146.6. IR (KBr, cm−1) 447, 515, 532, 546, 615, 664, 692, 748, 783, 889, 1117, 1157, 1179, 1323, 1400, 1425, 1450, 1495, 3034, 3267. HRMS (FAB+) m/z 416.1429 (M+H, C24H22N3O2S requires 416.1433).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:17][O:18][C:19](=[O:22])[CH2:20]Br.O>CC(C)=O>[CH3:17][O:18][C:19](=[O:22])[CH2:20][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)COc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Initially charge 50 g (359.4 mmol) of 3-nitrophenol and 175.67 g (539 mmol) of caesium carbonate in 1.0 liter of acetone and add 71.5 g (467.3 mmol) of bromoacetic acid methyl ester. Stir the mixture at 50° C. for 1 h and, after cooling, pour onto 7.5 liters of water. Stir the suspension for 30 min, then filter off with suction and wash the filter residue with water. Dry the solid in a drying cabinet at 50° C. and 100 mbar. 64.3 g (84.7% of theory) of the target compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl.O=O.[CH3:12][OH:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:2]3[C:7]([C:12](=[O:13])[C:3]=2[CH:4]=1)=[CH:6][C:5]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:12](=[O:13])[C:4]=1[CH:3]=3
Reactant: CO
Reactant: Cc1ccc(N)cc1
Agent: Cl
Agent: O=O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
1 Mole of 1,4-cyclohexanedione-2,5-di(methyl carboxylate), methanol whose weight was 10 times the weight of the 1,4-cyclohexanedione-2,5-di(methyl carboxylate), 2.53 mol of p-toluidine and 0.1 mol of hydrochloric acid were allowed to react at 65°-100° C. for 3 hours while they were substantially not in contact with oxygen, and the formed product was recovered by filtration and washed. This product was further heated to 250°-268° C. in a dimethylnaphthalene isomer mixture while it was substantially not in contact with oxygen, and the resultant product was recovered by filtration and washed. Added thereto were ethylene glycol monoethyl ether whose amount was 7 times the weight thereof and 50% caustic soda in such an amount that was 18% based on the total amount of the mixture. Then, sodium m-nitrobenzenesulfonate was added for oxidation, and the formed product was recovered by filtration and washed to give a crude 2,9-dimethylquinacridone having a purity of at least 99%. The crude 2,9-dimethylquinacridone obtained in this Referential Example was used in the following Examples.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][CH2:15][C:16]#[CH:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:17]#[C:16][CH2:15][CH2:14][C:13]([O:19][CH3:20])=[O:18])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])=[O:7]
Reactant: C#CCCC(=O)OC
Reactant: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)CCC#Cc1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-nitrobenzaldehyde (460 mg), Pd(PPh3)2Cl2 (70 mg), and CuI (38 mg), methyl pent-4-ynoate (269 mg) in TEA(5.0 mL) was stirred at room temperature until the reaction was completed. The crude residue was purified by a silica gel flash chromatography (15% EtOAc in hexanes), affording methyl 5-(4-formyl-3-nitrophenyl)pent-4-ynoate. ESI-MS m/z 262.23 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:7]=2[S:6](=[O:17])[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[NH:3]1>[OH-].[Na+].O1CCCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[S:6](=[O:17])[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1NC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1NC2=O
Reaction time: 8 h

Procedure:
Stir the oxide from Step A in a mixture of 5 cc of aqueous sodium hydroxide and 10 cc of tetrahydrofuran for 15 minutes. Evaporate the tetrahydrofuran, dilute with water. Filter and acidify the filtrate. Separate the solids by filtration and dry in vacuo at 50° C. Suspend the product in water. Stir overnight, filter and dry at 60° C. to obtain the title product (Yield 605 mg).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC(=O)C=Cc1cc(F)ccc1C
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (5.9 g) was added at room temperature diethyl malonate (14.0 g), and then added little by little 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g), and the mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (46 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (46 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (8.6 g) as colorless crystals.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[CH:25]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:35])([F:33])[F:34])[O:1][N:2]=[C:3]([C:4]3[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=3)[CH2:31]2)[CH:27]=[C:26]([Cl:36])[CH:25]=1
Reactant: CC(=O)NCc1ccc(C=NO)cc1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
N-{4-[(hydroxyimino)methyl]benzyl}acetamide (0.5 g) was dissolved in N,N-dimethylformamide (20 mL), N-chlorosuccinimide (0.38 g) was added to this solution, and the mixture was stirred for two hours at room temperature. To the reaction solution, 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (0.75 g) was added, and after the mixture was cooled to 0° C., a solution of triethylamine (0.58 g) in N,N-dimethylformamide (2 mL) was added dropwise to the mixture, which was then stirred for 8 hours at room temperature. After addition of water and extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield N-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamide (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: N#Cc1nc(N)nc(Nc2ccccc2)n1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1nc(N)nc(N(CC2CC2)c2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-6-phenylamino-[1,3,5]triazine-2-carbonitrile (prepared in an analogous manner to Intermediate 5, 160 mg, 0.75 mmol) in DMF (6 mL) was added potassium carbonate (207 mg, 150 μmol) followed by bromomethyl-cyclopropane (111 mg, 830 μmol). The mixture was heated at 120 C for 3 h, allowed to cool to room temperature before extracting into ethyl acetate (10 mL) and washing with water (3×10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound, which was used without further purification (300 mg, >100%). Method C HPLC-MS: MH+ requires m/z=267. Found: m/z=267, Rt=1.38 min (43%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][O:23][CH:24]([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26]>>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[CH:24]([O:23][CH3:22])[C:28]([NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:36])[F:35])=[O:29])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: COC(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: COC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2-methoxy-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-methoxy-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:18][S:19]([O:9][CH2:8][C:5]1[C:4]([F:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ncc(Br)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(5-Bromo-3-fluoropyridin-2-yl)methanol (0.20 g, 0.99 mmol) was dissolved in dichloromethane (5 mL), cooled to 0° C. and treated with triethylamine (0.15 mL, 1.1 mmol, 1.1 equiv) and methanesulfonyl chloride (0.085 mL, 1.1 mmol, 1.1 equiv). After 15 minutes, the mixture was diluted with dichloromethane (100 mL) and washed once with sodium bicarbonate (20 mL, aqueous saturated) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.Br[CH2:32][N:33]1[C:37](=[O:38])[C:36]2[C:39]([CH:45]([CH3:47])[CH3:46])=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:35]=2[S:34]1(=[O:49])=[O:48]>CO.O>[CH:45]([C:39]1[C:36]2[C:37](=[O:38])[N:33]([CH2:32][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[CH:11]=3)[S:34](=[O:49])(=[O:48])[C:35]=2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1)([CH3:47])[CH3:46]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: Oc1cc(-c2ccncc2)nn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(-c3ccncc3)nn1-c1ccc(Cl)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-(4-pyridyl)-5-hydroxy pyrazole (406 mg; 1.49 mmol) and Cs2CO3 (243 mg; 0.75 mmol) in methanol (8 ml) was stirred at room temperature for 4 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To the above residue was added 7 ml of DMF and 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (519 mg, 1.49 mmol) and the resulting mixture was stirred at room temperature for 5 hours and poured into water. The above mixture was extracted with methylene chloride (3×), the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 33-50% ethyl acetate/hexane; 12-50% methylene chloride/acetone) and recrystallized from methylene chloride/hexane to afford 401 mg (50%) of 4-isopropyl-6-methoxy-2-[1-(4-chlorophenyl)-3-(4-pyridyl) pyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =4-pyridyl; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. >190° C. (dec.).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[S:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH:47][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:40][CH:39]=1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 406 (M+Na+, 46), 384 (M+H+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:9]=1.[CH2:30]([O:32][C:33](=[O:47])[C@@H:34]([CH3:46])[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[CH:36]=1)[CH3:31].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:30]([O:32][C:33](=[O:47])[C@@H:34]([CH3:46])[C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:10]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:9]=3)[CH:41]=2)[CH:36]=1)[CH3:31]
Reactant: CCOC(=O)[C@@H](C)c1ccc2cc(O)ccc2c1
Reactant: BrCCCCCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](C)c1ccc2cc(OCCCCCCc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)ccc2c1
Yield: 87 %

Procedure:
A mixture of 2.2 g (4.86 mmol) of 1-(6-bromohexyl)-3,4-bis(phenylmethoxy)benzene, 1.0 g (4.1 mmol) of (S)-alpha-methyl-6-hydroxy-2-naphthaleneacetic acid ethyl ester, 0.68 g (4.5 mmol) sodium iodide and 2.4 g (17.4 mmol) of potassium carbonate in 50 mL of acetone-50 mL of dimethylformamide was stirred at reflux for 23 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified by HPLC using 10% ethyl acetate-hexane to give 2.2 g (87% yield) of (S)-alpha-methyl-6-[6-[3,4-bis(phenylmethoxy)-phenyl]hexyloxy]-2-naphthaleneacetic acid ethyl ester as an oil. The nmr was consistent with the structure.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]2[C:10]([C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:24]1[CH:28]=[C:27]([C:29]([OH:34])([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:26][N:25]=1)CCC>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.O1CCOCC1>[OH:34][C:29]([C:27]1[NH:26][N:25]=[C:24]([C:2]2[N:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]3[C:10]([C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][NH:8][C:7]=23)[CH:28]=1)([CH2:32][CH3:33])[CH2:30][CH3:31]
Reactant: COC(=O)C(=O)c1c[nH]c2c(Cl)ncc(OC)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(O)(CC)CC)[nH]n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCC(O)(CC)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)OC)c[nH]c23)n[nH]1
Temperature: 115 °C
Yield: 72.1 %

Procedure:
To a sealable flask containing methyl 2-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.070 g, 0.262 mmol) and 3-(3-(tributylstannyl)-1H-pyrazol-5-yl)pentan-3-ol (0.116 g, 0.262 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol). 1,4-Dioxane (5 ml) was added and the mixture was flushed with N2. The tube was sealed, and the mixture was heated to 115° C. After 16 h of heating, the mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was diluted with MeOH and was filtered through a pad of celite to remove any solids. The solution was concentrated again under reduced pressure and the residue was dissolved in DMF and was purified by prep HPLC to give the product, methyl 2-(7-(5-(3-hydroxypentan-3-yl)-1H-pyrazol-3-yl)-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.073 g, 0.189 mmol, 72.2% yield) as an off-white solid. LCMS: m/e 387.19 (M+H)+, ret time 1.075 min (method 3).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)C(O)=O)C.C(OC(=O)CCCCC1CCCCCC1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:12]1([CH2:11][CH2:10][CH2:9][CH2:5][CH2:4][OH:3])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)C(CCCC1CCCCCC1)C(=O)O
Agent: CCOC(=O)CCCCC1CCCCCC1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCCC1CCCCCC1

Procedure:
The starting material 5-cycloheptylpentan-1-ol is obtained as follows: cycloheptylpropylmalonic acid ethyl ester is heated to 180° C. for one hour. The resulting 5-cycloheptylvaleric acid ethyl ester [bp 80°-82° C. at 0.008 mm Hg (1.0 Pa)] is reduced with lithium aluminum hydride in tetrahydrofuran to yield 5-cycloheptylpentan-1-ol [bp 92°-94° C. at 0.008 mm Hg (1.0 Pa)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][C:34]=4[CH3:46])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][C:34]=4[CH3:46])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:13])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)/C=C/c1cnc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)c(C)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cnc(N2CCN(c3ncc(-c4cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c4)cn3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Ethyl (2E)-3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]acrylate (250 mg) was dissolved in EtOH (4 ml), and 10% Pd/C (80 mg) was added thereto under a hydrogen atmosphere at 1 atm, followed by stirring at room temperature overnight. The mixture was filtrated using Celite as a filtration assistant to remove the catalyst, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 3-[6-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-5-methylpyridin-3-yl]propanoate (163 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].F[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2]
Reactant: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
A mixture of 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (100 mg, 0.34 mmol), 2-fluoro-6-trifluoromethylpyridine (68 mg, 0.41 mmol), and potassium carbonate (110 mg, 0.69 mmol) in N,N-dimethylformamide (3 ml) is heated to 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid, diluted with dichloromethane and filtered through a phase separation cartridge. The organic phase is collected. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give 4-[2-ethyl-5-(6-trifluoromethylpyridin-2-yloxy)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione.